3-quinuclidinyl heteroatom bridged biaryl derivatives

ABSTRACT

Compounds of formula: 
                         
or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein: A and G are each independently N or N + —O − ; m and n are each independently 0, 1, or 2; X 1  and X 3  are each independently O, S, and —N(R 1 )—; X 2  is O, S, —N(R 1 )—, —N(Ar 2 )—and —N(R 2 )C(O)—; Ar 1  is a six-membered aromatic ring; Ar 2  is cyclohexyl or a mono- or bicyclic aromatic ring, and R 13  is hydrogen, alkyl, or halogen, as defined herein. The compounds are useful in treating conditions or disorders prevented by or ameliorated by nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formulas (I) and (II) and methods for using such compounds and compositions.

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/531,862, filed Dec. 22, 2003, which is incorporated hereinby reference.

TECHNICAL FIELD

The invention relates to 3-quinuclidinyl heteroatom bridged biarylderivatives, compositions comprising such compounds, and methods oftreating conditions and disorders using such compounds and compositions.

DESCRIPTION OF RELATED TECHNOLOGY

Nicotinic acetylcholine receptors (nAChRs) are widely distributedthroughout the central (CNS) and peripheral (PNS) nervous systems. Suchreceptors play an important role in regulating CNS function,particularly by modulating release of a wide range of neurotransmitters,including, but not necessarily limited to acetylcholine, norepinephrine,dopamine, serotonin, and GABA. Consequently, nicotinic receptors mediatea very wide range of physiological effects, and have been targeted fortherapeutic treatment of disorders relating to cognitive function,learning and memory, neurodegeneration, pain and inflammation, psychosisand sensory gating, mood, and emotion, among others.

Many subtypes of the nAChR exist in the CNS and periphery. Each subtypehas a different effect on regulating the overall physiological function.Typically, nAChRs are ion channels that are constructed from apentameric assembly of subunit proteins. At least 12 subunit proteins,α2-α10 and β2-β4, have been identified in neuronal tissue. Thesesubunits provide for a great variety of homomeric and heteromericcombinations that account for the diverse receptor subtypes. Forexample, the predominant receptor that is responsible for high affinitybinding of nicotine in brain tissue has composition (α4)₂(β2)₃ (the α4β2subtype), while another major population of receptors is comprised ofthe homomeric (α7)₅ (the α7 subtype).

Certain compounds, like the plant alkaloid nicotine, interact with allsubtypes of the nAChRs, accounting for the profound physiologicaleffects of this compound. While nicotine has been demonstrated to havemany beneficial properties, not all of the effects mediated by nicotineare desirable. For example, nicotine exerts gastrointestinal andcardiovascular side effects that interfere at therapeutic doses, and itsaddictive nature and acute toxicity are well-known. Ligands that areselective for interaction with only certain subtypes of the nAChR offerpotential for achieving beneficial therapeutic effects with an improvedmargin for safety.

The α7 nAChRs have been shown to play a significant role in enhancingcognitive function, including aspects of learning, memory and attention(Levin, E. D., J. Neurobiol. 53: 633–640, 2002). For example, α7 nAChRshave been linked to conditions and disorders related to attentiondeficit disorder, attention deficit hyperactivity disorder (ADHD),Alzheimer's disease (AD), mild cognitive impairment, senile dementia,dementia associated with Lewy bodies, dementia associated with Down'ssyndrome, AIDS dementia, Pick's Disease, as well as cognitive deficitsassociated with schizophrenia, among other systemic activities. Theactivity at the α7 nAChRs can be modified or regulated by theadministration of α7 nAChR ligands. The ligands can exhibit antagonist,agonist, partial agonist, or inverse agonist properties. Thus, α7ligands have potential in treatment of various cognitive disorders.

Although various classes of compounds demonstrating α7 nAChR-modulatingactivity exist, it would be beneficial to provide additional compoundsdemonstrating activity at the α7 nAChRs that can be incorporated intopharmaceutical compositions useful for therapeutic methods.Specifically, it would be beneficial to provide compounds that interactselectively with α7-containing neuronal nAChRs compared to othersubtypes.

SUMMARY OF THE INVENTION

The invention is directed to 3-quinuclidinyl heteroatom bridged biarylcompounds as well as compositions comprising such compounds, and methodof using the same. Compounds of the invention have the formula:

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein:

A is N or N⁺—O⁻;

n is 0, 1, or 2;

X¹ is selected from the group consisting of O, S, and —N(R¹)—

—X² is selected from the group consisting of O, S, —N(R¹)—, —N(Ar²)—,and —N(R²)C(O)—;

Ar¹ is a group of the formula:

Ar² is cycloalkyl, or Ar² is a group of the formula:

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of N and —C(R³);

Y⁵, Y⁶, Y⁷, Y⁸, and Y⁹ are each independently selected from the groupconsisting of N and —C(R⁶);

Y¹⁰ is selected from the group consisting of —N(R⁹), O and S;

Y¹¹ Y¹², Y¹³, and Y¹⁴ are each independently selected from the groupconsisting of N, C and —C(R⁶); provided that one of Y¹¹, Y¹², Y¹³, andY¹⁴ is C and formula (c) is attached to X² or the nitrogen atom of—N(Ar²)— through one of Y¹¹, Y¹², Y¹³, and Y¹⁴ that is represented by C;

Z¹ is independently selected from O, S, —N(R⁹), —C(R¹⁰) and—C(R¹⁰)(R^(10a));

Z² and Z³ are each independently selected from the group consisting ofN, C and —C(R¹²); provided that zero or one of Z² and Z³ is C; andprovided that when Z¹ is —C(R¹⁰), then Z² and Z³ are other than C; andfurther provided that when one of Z² or Z³ is C, then Z¹ is other than—C(R¹⁰);

Z⁴, Z⁵, Z⁶ and Z⁷ are independently selected from the group consistingof C and —C(R¹¹); provided that zero or one of Z⁴, Z⁵, Z⁶ and Z⁷ is C;wherein

when one of Z⁴, Z⁵, Z⁶ and Z⁷ is C, then formula (d) is attached to X²or the nitrogen atom of —N(Ar²)— through one of Z⁴, Z⁵, Z⁶ and Z⁷ thatis represented by C; Z¹ is other than —C(R¹⁰); and Z² and Z³ are otherthan C; or

when Z¹ is —C(R¹⁰), then formula (d) is attached to X² or the nitrogenatom of —N(Ar²)— through the C atom of —C(R¹⁰),\; Z⁴, Z⁵, Z⁶, and Z⁷ are—C(R¹¹); an are other than C; or

when one of Z² or Z³ is C, then formula (d) is attached to X² or thenitrogen atom of —N(Ar²)— through Z² or Z³ represented by C; Z¹ is otherthan —C(R¹⁰); and Z⁴, Z⁵, Z⁶, and Z⁷ are —C(R¹¹);

R¹ and R² at each occurrence are each independently selected from thegroup consisting of hydrogen and alkyl;

R³ at each occurrence is independently selected from the groupconsisting of hydrogen, halo, alkyl, aryl, —OR⁴, and —NHR⁵;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, andarylsulfonyl;

R⁶ at each occurrence is independently selected from the groupconsisting of hydrogen, halo, haloalkyl, alkyl, aryl, alkylcarbonyl,—OR⁷, and —NHR⁸;

R⁷ and R⁸ are each independently selected from the group consisting ofhydrogen, alkyl, 1-aza-bicyclo[2.2.2]oct-3-yl, amino, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, and arylsulfonyl; and

R⁹, R¹⁰, R^(10a), R¹¹, and R¹² at each occurrence are each independentlyselected from the group consisting of hydrogen, alkyl, aryl,alkylcarbonyl, and arylcarbonyl.

The invention also relates to compounds of formula:

or pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, wherein G is N or N⁺—O⁻; X³ is —N(R¹⁴)—, O, or S; m is 0, 1, or2; R¹⁴ is hydrogen or alk R¹³ is hydrogen, alkyl, or halogen.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to nAChR activity, and more particularly α7 nAChRactivity.

Yet another aspect of the invention relates to a method of selectivelymodulating to nAChR activity, for example α7 nAChR activity. The methodis useful for treating and/or preventing conditions and disordersrelated to α7 nAChR activity modulation in mammals. More particularly,the method is useful for conditions and disorders related to attentiondeficit disorder, attention deficit hyperactivity disorder (ADHD),Alzheimer's disease (AD), mild cognitive impairment, senile dementia,AIDS dementia, Pick's Disease, dementia associated with Lewy bodies,dementia associated with Down's syndrome, amyotrophic lateral sclerosis,Huntington's disease, diminished CNS function associated with traumaticbrain injury, acute pain, post-surgical pain, chronic pain, inflammatorypain, neuropathic pain, infertility, need for new blood vessel growthassociated with wound healing, need for new blood vessel growthassociated with vascularization of skin grafts, and lack of circulation,more particularly circulation around a vascular occlusion, among othersystemic activities.

The compounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “acyl” as used herein means an alkyl group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of acyl include, but are notlimited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl,and 1-oxopentyl.

The term “acyloxy” as used herein means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of acyloxy include, but are not limited to,acetyloxy, propionyloxy, and isobutyryloxy.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through another alkoxygroup, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, represented by —C(O)—, as defined herein. Representativeexamples of alkoxycarbonyl include, but are not limited to,methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxyimino” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an imino group,as defined herein. Representative examples of alkoxyimino include, butare not limited to, ethoxy(imino)methyl and methoxy(imino)methyl.

The term “alkoxysulfonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl and propoxysulfonyl.

The term “alkyl” means a straight or branched chain hydrocarboncontaining from 1 to 6 carbon atoms. Representative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, and n-hexyl.

The term “alkylcarbonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonyloxy” as used herein means an alkylcarbonyl group,as defined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of alkylcarbonyloxy include, butare not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylsulfonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup, as defined herein. Representative examples of alkylsulfonylinclude, but are not limited to, methylsulfonyl and ethylsulfonyl.

The term “alkylthio” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “amido” as used herein means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of amidoinclude, but are not limited to, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

The term “aryl” as used herein means a monocyclic or bicyclic aromaticring system. Representative examples of aryl include, but are notlimited to, phenyl and naphthyl.

The aryl groups of this invention are substituted with 0, 1, 2, 3, 4, or5 substituents independently selected from acyl, acyloxy, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amino, carboxy, cyano,formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto,nitro, thioalkoxy, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, (NR_(A)R_(B))carbonyl, and (N R_(A)R_(B))sulfonyl.

The term “arylcarbonyl” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, (phenyl)carbonyl and(naphthyl)carbonyl.

The term “arylsulfonyl” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup, as defined herein. Representative examples of arylsulfonylinclude, but are not limited to, phenylsulfonyl,(methylaminophenyl)sulfonyl, (dimethylaminophenyl)sulfonyl, and(naphthyl)sulfonyl.

The term “carbonyl” as used herein means a —C(O)— group.

The term “carboxy” as used herein means a —CO₂H group.

The term “cyano” as used herein means a —CN group.

The term “formyl” as used herein means a —C(O)H group.

The term “halo” or “halogen” means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl” as used herein means an aromatic five- orsix-membered ring containing 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. The heteroaryl groups areconnected to the parent molecular moiety through a carbon or nitrogenatom. Representative examples of heteroaryl include, but are not limitedto, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl.

The heteroaryl groups of the invention are substituted with 0, 1, 2, or3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy,hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “bicyclic heteroaryl” refers to fused aromatic nine- andten-membered bicyclic rings containing 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a tautomerthereof. The bicyclic heteroaryl groups are connected to the parentmolecular moiety through a carbon or nitrogen atom. Representativeexamples of bicyclic heteroaryl rings include, but are not limited to,indolyl, benzothiazolyl, benzofuranyl, isoquinolinyl, and quinolinyl.Bicyclic heteroaryl groups of the invention are substituted with 0, 1,2, or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy,hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “hydroxy” as used herein means an —OH group.

The term “hydroxyalkyl” as used herein means at least one hydroxy group,as defined herein, is appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term “hydrazine” as used herein means a —NH—NH₂ group.

The term “mercapto” as used herein means a —SH group.

The term “nitro” as used herein means a —NO₂ group.

The term “—NR_(A)R_(B)” as used herein means two groups, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are each independently hydrogen, alkyl,alkylcarbonyl, or formyl. Representative examples of —NR_(A)R_(B)include, but are not limited to, amino, methylamino, acetylamino, andacetylmethylamino.

The term “(NR_(A)R_(B))alkyl” as used herein means a —NR_(A)R_(B) group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of(NR_(A)R_(B))alkyl include, but are not limited to, (amino)methyl,(dimethylamino)methyl, and (ethylamino)methyl.

The term “(NR_(A)R_(B))alkoxy” as used herein means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples of(NR_(A)R_(B))alkoxy include, but are not limited to, (amino)methoxy,(dimethylamino)methoxy, and (diethylamino)ethoxy.

The term “(NR_(A)R_(B))carbonyl” as used herein means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(NR_(A)R_(B))sulfonyl” as used herein means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(A)R_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl, and(ethylmethylamino)sulfonyl.

The term “sulfonyl” as used herein means a —S(O)₂— group.

The term “thioalkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of thioalkoxy include, but are no limited to,methylthio, ethylthio, and propylthio.

Although typically it may be recognized that an asterisk is used toindicate that the exact subunit composition of a receptor is uncertain,for example α3b4* indicates a receptor that contains the α3 and β4proteins in combination with other subunits, the term α7 as used hereinis intended to include receptors wherein the exact subunit compositionis both certain and uncertain. For example, as used herein α7 includeshomomeric (α7)₅ receptors and α7* receptors, which denote a nAChRcontaining at least one α7 subunit.

Compounds of the Invention

Compounds of the invention can have the formula (I) as described above.More particularly, compounds of formula (I) can include, but are notlimited to, compounds wherein Ar¹ is a group of the formula:

In a group of formula (a), Y¹, Y², Y³, and Y⁴ are each independentlyselected from the group consisting of N and —C(R³), wherein R³ at eachoccurrence is independently selected from the group consisting ofhydrogen, halo, alkyl, aryl, —OR⁴ and —NHR⁵. Preferably, at least one ofY¹, Y², Y³, and Y⁴ is —C(R³), such that group of formula (a) contains 0,1, 2, or 3 nitrogen atoms.

Specific examples of groups for Ar¹ are, for example,

wherein R³ is as previously defined for compounds of formula (I).

Compounds of the invention can include those wherein Ar² is cycloalkyl,preferably cyclohexyl, or Ar² is a group of the formula:

wherein Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, Y⁹, Y¹⁰, Y¹¹, Y¹², Y¹³, Y¹⁴, Z¹,Z², Z³, Z⁴, Z⁵, Z⁶, and Z⁷ are as previously described for compounds offormula (I).

Specific examples of groups for Ar² in a compound of formula (I) are,for example, cycloalkyl,

wherein:

r is 0, 1,3,4 or 5;

s is 0, 1, 2 or 3;

t is 0, 1 ,2,3 or 4;

Y¹⁰ is selected from the group consisting of —N(R⁹), O and S;

one of Y¹² and Y¹³ is N, C or —C(R⁶), and the other is C or —C(R⁶);

Y¹¹ and Y¹⁴ are each independently selected from the group consisting ofC and —C(R⁶); provided that one of Y¹¹ and Y¹⁴ or one of Y¹² and Y¹³ isC and formula (C) is attached to X² or the nitrogen atom of —N(Ar²)—through one of Y¹¹, Y¹², Y¹³, and Y¹⁴ that is represented by C; and

Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, R⁶, and R⁹ are as described for compounds offormula (I).

More specific examples of groups for Ar² in a compound of formula (I)are, for example, cycloalkyl, preferably cyclohexyl,

wherein:

Z² and Z³ are independently N, C or —C(R¹²); provided that zero or oneof Z² and Z³ is C;

Z⁴, Z⁵, Z⁶, and Z⁷ are independently selected from the group consistingof C and —C(R¹¹); provided that zero or one of Z⁴, Z⁵, Z⁶, and Z⁷ is C;wherein

when one of Z⁴, Z⁵, Z⁶, and Z⁷ is C, then each of formulas (4-vi) and(4-vii) is attached to X² or the nitrogen atom of —N(Ar²)— through oneof Z⁴, Z⁵, Z⁶, and Z⁷ that is represented by C, and Z² and Z³ are each—C(R¹²); or

when one of Z² or Z³ is C, then each of formulas (4-vi) and (4-vii) isattached to X² or the nitrogen atom of —N(Ar²)— through Z² or Z³represented by C, and Z⁴, Z⁵, Z⁶, and Z⁷ are —C(R¹¹);

R⁶ is selected from the group consisting of hydrogen, fluoro,trifluoromethyl, hydroxy, 1-aza-bicyclo[2.2.2]oct-3-yloxy,1-aza-bicyclo[2.2.2]oct-3-ylamino, isopropoxy, bromo, chloro, iodo,methyl, hydrazino, and amino;

R¹² is selected from the group consisting of hydrogen, methyl andphenyl; and

R⁹ and R¹¹ are as described for compounds of formula (I).

Specific embodiments of compounds of formula (I) contemplated as part ofthe invention include, but are not limited to:

-   3-(3-phenoxyphenoxy)quinuclidine;-   3-(4-phenoxyphenoxy)quinuclidine;-   (3R)-3-(4-phenoxyphenoxy)quinuclidine;-   (3S)-3-(4-phenoxyphenoxy)quinuclidine;-   3-{4-[4-(trifluoromethyl)phenoxy]phenoxy}quinuclidine;-   3-[4-(4-fluorophenoxy)phenoxy]quinuclidine;-   4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenoxy]phenol;-   4-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenoxy}phenol;-   4-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]thio}phenol;-   4-({4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}thio)phenol;-   3-{4-[(4-isopropoxyphenyl)thio]phenoxy}quinuclidine;-   3-[4-(pyridin-3-yloxy)phenoxy]quinuclidine;-   3-[4-(thien-3-yloxy)phenoxy]quinuclidine;-   3-{4-[(5-bromopyrimidin-2-yl)oxy]phenoxy}quinuclidine;-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-phenylamine;-   N-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-N-phenylamine;-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]pyridin-3-amine;-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]benzamide;-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-cyclohexylamine;-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-dithien-3-ylamine;-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-1,3-thiazol-2-yl-1,3-thiazol-2-amine-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-bis(1-benzothien-3-yl)amine;-   1-(5-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]amino}thien-2-yl)ethanone;-   N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-(4-methylthien-3-yl)amine;-   3-[(6-phenoxypyridazin-3-yl)oxy]quinuclidine;-   3-[(5-phenoxypyridin-2-yl)oxy]quinuclidine;-   3-[(5-phenoxypyrimidin-2-yl)oxy]quinuclidine;-   N-(4-phenoxyphenyl)quinuclidin-3-amine;-   N-[4-(4-chlorophenoxy)phenyl]quinuclidin-3-amine;-   N-[4-(4-methylphenoxy)phenyl]quinuclidin-3-amine;-   N-[4-(4-aminophenoxy)phenyl]quinuclidin-3-amine;-   N-1-azabicyclo[2.2.2]oct-3-yl-N′-phenylbenzene-1,4-diamine;-   3-[(4-phenoxyphenyl)thio]quinuclidine;-   N-[4-(1-azabicyclo[2.2.2]oct-3-ylthio)phenyl]-N-phenylamine;-   4,4′-di(1-aza-bicyclo[2.2.2]oct-3-yloxy)-diphenyl ether;-   4,4′-di[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-diphenyl thioether;-   4,4′-di(1-aza-bicyclo[2.2.2]oct-3-yl-amino)-diphenyl thioether;-   3-[4-(4-iodo-phenoxy)-phenoxy]-1-aza-bicyclo[2.2.2]octane;-   {4-[4-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-phenoxy]-phenyl}-hydrazine;-   3-[4-(2-methyl-3-phenyl-1H-indol-5-yloxy)-phenoxy]-1-aza-bicyclo[2.2.2]octane;    and-   3-[6-(4-iodo-phenoxy)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;    or pharmaceutically acceptable salts, esters, amides, and prodrugs    thereof.

The invention also relates to compounds of formula:

or pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, wherein G is N or N⁺—O⁻; X³ is —N(R¹⁴)—, O, or S; m is 0, 1, or2; R¹⁴ is hydrogen or alk R¹³ is hydrogen, alkyl, or halogen.Preferably, R¹³ is iodo or hydrogen.

Specific embodiments of compounds of formula (II) contemplated as partof the invention include, but are not limited to:

-   2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-8-iodo-6H, 1    2H-5,11-methano-dibenzo[b,f][-   2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-6H,    12H-5,11-methano-dibenzo[b,f][1,5]diazo    or pharmaceutically acceptable salts, esters, amides, and prodrugs    thereof.

Compound names are assigned by using AUTONOM naming software, which isprovided by MDL Information Systems GmbH (formerly known as BeilsteinInformationssysteme) of Frankfurt, Germany, and is part of the CHEMDRAW®ULTRA v. 6.0.2 software suite.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralelement. The terms “R” and “S” used herein are configurations as definedin IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13–30. The inventioncontemplates various stereoisomers and mixtures thereof and arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Methods for Preparing Compounds of the Invention

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: Ac foracetyl; Bu for butyl; dba for dibenzylidene acetone; DEAD for diethylazodicarboxylate; DMSO for dimethylsulfoxide; EtOAc for ethyl acetate;EtOH for ethanol; Et₃N for triethylamine; Et₂O for diethyl ether; HPLCfor high pressure liquid chromatography; ^(i)Pr for isopropyl; Me formethyl; MeOH for methanol; NBS for N-bromosuccinimide; OAc for acetoxy;o-tol. for o-toluene; Ph for phenyl; tBu for tert-butyl; THF fortetrahydrofuran; NMP for 1-methyl-pyrrolidin-2-one; and TMHD for2,2,6,6-tetramethylheptane-3,5-dione.

The reactions exemplified in the schemes are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. The described transformations mayrequire modifying the order of the synthetic steps or selecting oneparticular process scheme over another in order to obtain a desiredcompound of the invention, depending on the functionality present on themolecule.

Nitrogen protecting groups can be used for protecting amine groupspresent in the described compounds. Such methods, and some suitablenitrogen protecting groups, are described in Greene and Wuts (ProtectiveGroups In Organic Synthesis, Wiley and Sons, 1999). For example,suitable nitrogen protecting groups include, but are not limited to,tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), acetyl,and trifluoracetyl. More particularly, the Boc protecting group may beremoved by treatment with an acid such as trifluoroacetic acid orhydrochloric acid. The Cbz and Bn protecting groups may be removed bycatalytic hydrogenation. The acetyl and trifluoracetyl protecting groupsmay be removed by a hydroxide ion.

The methods described below can entail use of various enantiomers. Wherethe stereochemistry is shown in the Schemes, it is intended forillustrative purposes only.

Quinuclidine ethers of formula (3), wherein Ar¹, X², and Ar² are asdefined for formula (I), can be obtained by the methods described inScheme 1. Compounds of formula (1) can be treated with 3-quinuclidinolin the presence of a phosphine, for example triphenylphosphine, anddiethyl azodicarboxylate to provide compounds of formula (3).Alternatively, compounds of formula (2), wherein X² and Ar² are asdefined for a compound of formula (I), can be reacted with CuI, Cs₂CO₃and 1,10-phenanthroline as described in Org. Lett. 2002, 4, 973, toprovide a desired compound of formula (3).

Quinuclidine ethers of general formula (11), (12), and (13), wherein Ar¹and Ar² are as defined in formula (I), can be prepared as described inScheme 2. 3-Quinuclidinol is treated with a halophenyl iodide of formula(5), wherein X′ is bromide or iodide, with CuI, Cs₂CO₃ and1,10-phenanthroline as described in Org. Lett., 2002, 4, 973, to obtaina halophenoxy quinuclidine of formula (7). Alternatively, a compound offormula (7) can be obtained by treating 3-quinuclidinol with a halophenyl alcohol of formula (6), wherein X′ is bromide or iodide, anddiethyl azodicarboxylate in the presence of a phosphine, such astriphenylphosphine.

Compounds of formula (7), wherein X′ are bromide or iodide, can betreated with the compound of formula (8) with CuCl, Cs₂CO₃ and TMHD inNMP to provide compounds of formula (11) as described in Org. Lett.2002, 4, 1623. Compounds of formula (7), wherein X′ are bromide oriodide, can be treated with an amine of a desired Ar² group of formula(9) with tris(dibenzylideneacetone)dipalladium (0) and Xantphos withsodium tert-butoxide in an organic solvent, such as toluene to providecompounds of formula (12) as described in Org. Lett. 2002, 4, 3481.Compounds of formula (7), wherein X′ is iodide, can be treated with athiol of a desired Ar² group of formula (10) with CuI, K₂CO₃ and1,2-ethanediol to provide compounds of formula (13) as described in Org.Lett. 2002, 4, 3517.

Quinuclidine ethers of formulas (23), (24), and (25), wherein Ar¹ is anitrogen-containing heteroaryl, for example pyridazine, and Ar² is asdefined for formula (I), can be prepared as shown in Scheme 3. A metalquinuclidinoxide of formula (20), wherein M is potassium or sodium, canbe reacted with a dihaloaromatic ring, for example, dichloropyridazine,of formula (21a), wherein Y¹ and Y² are bromide, chloride, or iodide,and X¹, X², and X³ are nitrogen or CH, to obtain a quinuclidine ether offormula (22). Alternatively, a compound of formula (22) can be obtainedby treating 3-quinuclidinol with a compound of formula (21b), wherein Y²is bromide, chloride, or iodide, with diethyl azodicarboxylate in thepresence of a phosphine, such as triphenylphosphine.

Compounds of formula (22), wherein Y² is bromide or iodide, can betreated with the compound of formula (8) with Cs₂CO₃, CuCl and TMHD inNMP to provide compounds of formula (23) as described in Org. Lett.2002, 4, 1623. Compounds of formula (22), wherein Y² is bromide oriodide, can be treated with an amine of a desired Ar² group of formula(9) with tris(dibenzylideneacetone)dipalladium (0)and Xantphos withsodium tert-butoxide in an organic solvent, such as toluene to providecompounds of formula (24) as described in Org. Lett. 2002, 4, 3481.Compounds of formula (22), wherein Y² is iodide, can be treated with athiol of a desired Ar² group of formula (10) with CuI, K₂CO₃ and1,2-ethanediol to provide compounds of formula (25) as described in Org.Lett. 2002, 4, 3517.

Compounds of formula (31), wherein Ar¹, X², and Ar² are as defined incompounds of formula (I), can be prepared as shown in Scheme 4.3-Quinuclidinone and an amine of formula (30), can be treated withsodium triacetoxy borohydride and Na₂SO₄ in acetic acid to provide aracemic compound of formula (31) as described in Tetrahedron Lett. 1996,37, 6045. The racemate of formula (31) can be resolved into itsrespective isomers by resolution with D-tartaric acid or via chiral HPLCchromatography on a Chiracel®-OD chromatography column using methodswell-known in the art to provide the (R)- and (S)-isomers of formulas(31), respectively.

Quinuclidine amine derivatives of formulas (40), (41), and (42), whereinAr¹, Ar², and R¹ are as defined for formula (I), can be prepared asshown in Scheme 5. 3-Quinuclidinone (35) and a haloarylamine of formula(36), wherein Y is bromide, chloride, or iodide, can be treated withsodium triacetoxy borohydride and Na₂SO₄ in acetic acid to provide aracemic compound of formula (39) as described in Tetrahedron Lett. 1996,37, 6045. The racemate of formula (39) can be resolved into itsrespective isomers by resolution with D-tartaric acid or via chiral HPLCchromatography on a Chiracel®-OD chromatography column using methodswell-known in the art to provide the (R)- and (S)-isomers of formula(39), respectively. Alternatively, a compound of formula (39) can beobtained by treating 3-aminoquinuclidine (37) with haloaromatic group asdescribed in formula (38) in Cs₂CO₃ in the presence of palladiumcatalyst, preferably in toluene.

Compounds of formula (39), wherein Y is bromide or iodide, can betreated with a compound of formula (8) with CuCl, TMHD and Cs₂CO₃ in NMPto provide compounds of formula (40) as described in Org. Lett. 2002, 4,1623. Compounds of formula (39), wherein Y is bromide or iodide, can betreated with an amine of a desired Ar² group of formula (9) withtris(dibenzylideneacetone)dipalladium (0) and Xantphos with sodiumtert-butoxide in an organic solvent, such as toluene, to providecompounds of formula (41) as described in Org. Lett. 2002, 4, 3481.Compounds of formula (39), wherein X′ is iodide, can be treated with athiol of a desired Ar² group of formula (10) with CuI, K₂CO₃ and1,2-ethanediol to provide compounds of formula (42) as described in Org.Lett. 2002, 4, 3517.

Quinuclidine sulfide derivatives of formulas (48), (49), and (50),wherein Ar¹, Ar², and R¹ are as defined for formula (I), can be preparedas shown in Scheme 6. 3-Chloroquinuclidine can be reacted with ahaloarylthiol of formula (46), wherein Y is bromide, chloride, oriodide, to provide a racemic compound of formula (47) as described in J.Med. Chem. 1999, 42, 1306. The racemate of formula (47) can be resolvedinto its respective isomers by resolution with D-tartaric acid or viachiral HPLC chromatography on a Chiracel®-OD chromatography column usingmethods well-known in the art to provide the (R)- and (S)-isomers offormula (47), respectively.

Compounds of formula (47), wherein Y is bromide or iodide, can betreated with a compound of formula (8) with CuCl, TMHD and Cs₂CO₃ in NMPto provide compounds of formula (48) as described in Org. Lett. 2002, 4,1623. Compounds of formula (47), wherein Y is bromide or iodide, can betreated with an amine of a desired Ar² group of formula (9) withtris(dibenzylideneacetone)dipalladium (0) and Xantphos with sodiumtert-butoxide in an organic solvent, such as toluene to providecompounds of formula (49) as described in Org. Lett. 2002, 4, 3481.Compounds of formula (47), wherein Y is iodide, can be treated with athiol of a desired Ar² group of formula (10) with CuI, K₂CO₃ and1,2-ethanediol to provide compounds of formula (50) as described in Org.Lett. 2002, 4, 3517.

Compounds of formula (53), wherein X² and Ar² are as defined forcompounds of formula (I), can be prepared as shown in Scheme 7.3,6-Dichloropyridazine can be treated with a compound of formula (51)and sodium hydroxide to provide compounds of formula (52). Compounds offormula (52) are reacted with potassium quinuclidinoxide to providecompounds of formula (53).

Quinuclidine ethers of general formula (56), wherein Ar¹ and X² are asdefined in formula (I), can be prepared as described in Scheme 8.Commercially available compounds of formula (55) can be converted tocompounds of formula (56) using the conditions employed in thetransformation of compounds of formula (21b) to compounds of formula(22) as described in Scheme 3.

Compounds of general formula (61), wherein Ar¹ is as defined in formula(I), can be prepared as described in Scheme. Commercially availableamines of formula (60) can be treated with quinuclidinone using theconditions for the transformation of compounds of formula (30) tocompounds of formula (31) as outlined in Scheme 4, to provide compoundsof formula (60).

Compounds of general formulas (65) and (67) wherein Ar¹, X², Ar² are asdefined in formula (I) can be obtained from compounds of formula (64) or(62) as described in Scheme 10. Compounds of formula (62) can be reactedwith 3-quinuclidinol using the conditions for the transformation ofcompounds of formula (2) to compounds of formula (3) as described inScheme 1, to provide compounds of formula (63). Alternatively, compoundsof formula (63) can be obtained from compounds of formula (64a), usingthe conditions employed for the conversion of compounds of formula (1)to compounds of formula (3) as described in Scheme 1. Reacting compoundsof formula (63) with a N-protected hydrazine such as hydrazinecarboxylicacid tert-butyl ester in the presence of a base such as cesiumcarbonate, and copper(I) iodide, provides compounds of formula (64).Deprotecting compounds of formula (64) in acidic medium such as aqueoushydrochloric acid or trifluoroacetic acid, provides compounds of formula(65). Compounds of formula (64) can be reacted with ketones of formula(66) in the presence of an acid such as toluene sulfonic acid orhydrochloric acid, followed by in situ cyclization to afford compoundsof formula (67).

Compounds of formula (71) can be obtained from compounds of formula (68)as described in Scheme 11. Reacting compounds of formula (68) withformaldehyde in the presence of trifluoroacetic acid provides compoundsof formula (69). The di-iodo compounds of formula (69) can be reactedwith 3-quinuclidinol using the reaction conditions used for theconversion of compounds of formula (2) to compounds of formula (3) asdescribed in Scheme 1, to provide compounds of formula (70).De-iodonation of compounds of formula (70) with hydrogen, in thepresence of palladium/carbon provides compounds of formula (71).

Compounds of formula (I) wherein A is N can be converted to compounds offormula (I) wherein A is N⁺—O⁻ by treatment with an oxidizing agent.Compounds of formula (II) wherein G is N can be converted to compoundsof formula (II) wherein G is N⁺—O⁻ using the same conditions. Examplesof the oxidizing agent include, but not limited to, aqueous hydrogenperoxide and m-chloroperbenzoic acid. The reaction is generallyperformed in a solvent such as, but not limited to, acetonitrile, water,dichloromethane, acetone or mixture thereof, preferably a mixture ofacetonitrile and water, at a temperature from about room temperature toabout 80° C., for a period of about 1 hour to about 4 days.

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

The compounds of the invention have at least one basic nitrogen wherebythe compound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric,gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic,phosphoric, sulfuric, citric, or hydroxybutyric acid, camphorsulfonic,malic, phenylacetic, aspartic, glutamic, and the like.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) or (II) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administration,including intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms can be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It also can bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug can depend upon its rateof dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, a parenterally administered drug formcan be administered by dissolving or suspending the drug in an oilvehicle.

Suspensions, in addition to the active compounds, can contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation also can be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They can optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials useful for delaying release of the activeagent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, eardrops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention also can be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants. Ophthalmicformulations, eye ointments, powders and solutions are also contemplatedas being within the scope of this invention. Aqueous liquid compositionsof the invention also are particularly useful.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides,” as used herein, include salts, zwitterions, estersand amides of compounds of formula (I) which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, are commensurate with a reasonable benefit/riskratio, and are effective for their intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester,” as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) can be preparedaccording to conventional methods. Pharmaceutically acceptable esterscan be appended onto hydroxy groups by reaction of the compound thatcontains the hydroxy group with acid and an alkylcarboxylic acid such asacetic acid, or with acid and an arylcarboxylic acid such as benzoicacid. In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyl iodide, benzyl iodide, cyclopentyl iodide. They alsocan be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide,” as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine can also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) can beprepared according to conventional methods. Pharmaceutically acceptableamides can be prepared from compounds containing primary or secondaryamine groups by reaction of the compound that contains the amino groupwith an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide.In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also can beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention can be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987).

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

Compounds and compositions of the invention are useful for modulatingthe effects of nAChRs, and more particularly α7 nAChRs. In particular,the compounds and compositions of the invention can be used for treatingand preventing disorders modulated by α7 nAChRs. Typically, suchdisorders can be ameliorated by selectively modulating the α7 nAChRs ina mammal, preferably by administering a compound or composition of theinvention, either alone or in combination with another active agent, forexample, as part of a therapeutic regimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for nAChRs, and moreparticularly α7 nAChRs. As α7 nAChRs ligands, the compounds of theinvention can be useful for the treatment and prevention of a number ofα7 nAChR-mediated diseases or conditions.

For example, α7 nAChRs have been shown to play a significant role inenhancing cognitive function, including aspects of learning, memory andattention (Levin, E. D., J. Neurobiol. 53: 633–640, 2002). As such, α7ligands are suitable for the treatment of cognitive disorders including,for example, attention deficit disorder, attention deficit hyperactivitydisorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment,senile dementia, AIDS dementia, Pick's Disease, dementia associated withLewy bodies, and dementia associated with Down's syndrome, as well ascognitive deficits associated with schizophrenia.

In addition, α7-containing nAChRs have been shown to be involved in theneuroprotective effects of nicotine both in vitro (Jonnala, R. B. andBuccafusco, J. J., J. Neurosci. Res. 66: 565–572, 2001) and in vivo(Shimohama, S. et al., Brain Res. 779: 359–363, 1998). Moreparticularly, neurodegeneration underlies several progressive CNSdisorders, including, but not limited to, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, Huntington'sdisease, dementia with Lewy bodies, as well as diminished CNS functionresulting from traumatic brain injury. For example, the impairedfunction of α7 nAChRs by β-amyloid peptides linked to Alzheimer'sdisease has been implicated as a key factor in development of thecognitive deficits associated with the disease (Liu, Q.-S., Kawai, H.,Berg, D. K., PNAS 98: 4734–4739, 2001). The activation of α7 nAChRs hasbeen shown to block this neurotoxicity (Kihara, T. et al., J. Biol.Chem. 276: 13541–13546, 2001). As such, selective ligands that enhanceα7 activity can counter the deficits of Alzheimer's and otherneurodegenerative diseases.

Schizophrenia is a complex disease that is characterized byabnormalities in perception, cognition, and emotions. Significantevidence implicates the involvement of α7 nAChRs in this disease,including a measured deficit of these receptors in post-mortem patients(Leonard, S. Eur. J. Pharmacol. 393: 237–242, 2000). Deficits in sensoryprocessing (gating) are one of the hallmarks of schizophrenia. Thesedeficits can be normalized by nicotinic ligands that operate at the α7nAChR (Adler L. E. et al., Schizophrenia Bull. 24: 189–202, 1998;Stevens, K. E. et al., Psychopharmacology 136: 320–327, 1998). Thus, α7ligands demonstrate potential in the treatment schizophrenia.

Angiogenesis, a process involved in the growth of new blood vessels, isimportant in beneficial systemic functions, such as wound healing,vascularization of skin grafts, and enhancement of circulation, forexample, increased circulation around a vascular occlusion.Non-selective nAChR agonists like nicotine have been shown to stimulateangiogenesis (Heeschen, C. et al., Nature Medicine 7: 833–839, 2001).Improved angiogenesis has been shown to involve activation of the α7nAChR (Heeschen, C. et al, J. Clin. Invest. 110: 527–536, 2002).Therefore, nAChR ligands that are selective for the α7 subtype offerimproved potential for stimulating angiogenesis with an improved sideeffect profile.

A population of α7 nAChRs in the spinal cord modulate serotonergictransmission that have been associated with the pain-relieving effectsof nicotinic compounds (Cordero-Erausquin, M. and Changeux, J.-P. PNAS98:2803–2807, 2001). The α7 nAChR ligands demonstrate therapeuticpotential for the treatment of pain states, including acute pain,post-surgical pain, as well as chronic pain states includinginflammatory pain and neuropathic pain. Moreover, α7 nAChRs areexpressed on the surface of primary macrophages that are involved in theinflammation response, and that activation of the α7 receptor inhibitsrelease of TNF and other cytokines that trigger the inflammationresponse (Wang, H. et al Nature 421: 384–388, 2003). Therefore,selective α7 ligands demonstrate potential for treating conditionsinvolving inflammation and pain.

The mammalian sperm acrosome reaction is an exocytosis process importantin fertilization of the ovum by sperm. Activation of an α7 nAChR on thesperm cell has been shown to be essential for the acrosome reaction(Son, J.-H. and Meizel, S. Biol. Reproduct. 68: 1348–1353 2003).Consequently, selective α7 agents demonstrate utility for treatingfertility disorders.

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting cognition,neurodegeneration, and schizophrenia.

Cognitive impairment associated with schizophrenia often limits theability of patients to function normally, a symptom not adequatelytreated by commonly available treatments, for example, treatment with anatypical antipsychotic. (Rowley, M. et al., J. Med. Chem. 44: 477–501,2001). Such cognitive deficit has been linked to dysfunction of thenicotinic cholinergic system, in particular with decreased activity atα7 receptors. (Friedman, J. I. et al., Biol Psychiatry, 51: 349–357,2002). Thus, activators of α7 receptors can provide useful treatment forenhancing cognitive function in schizophrenic patients who are beingtreated with atypical antipsychotics. Accordingly, the combination of anα7 nAChR ligand and an atypical antipsychotic would offer improvedtherapeutic utility. Specific examples of suitable atypicalantipsychotics include, but are not limited to, clozapine, risperidone,olanzapine, quietapine, ziprasidone, zotepine, iloperidone, and thelike.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal range from about 0.10 mg/kg body weight to about1 g/kg body weight. More preferable doses can be in the range of fromabout 0.10 mg/kg body weight to about 100 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

The compounds and processes of the invention will be better understoodby reference to the following examples and reference examples, which areintended as an illustration of and not a limitation upon the scope ofthe invention.

REFERENCE EXAMPLES Reference Example 1 (R)-3-quinuclidinol

(R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treatedwith NaOH aqueous solution(20%, 50 mL) at ambient temperature for 10min. It was then extracted with CHCl₃/PrOH (v. 10:1, 3×200 mL). Theextracts were combine, washed with brine (50 mL) and dried over MgSO₄.The drying agents were removed by filtration and the filtrates wasconcentrated under reduced pressure to give the title compound as whitesolid (15.5 g, yield, 99%). ¹H NMR (300 MHz, MeOH-d₄) δ 1.36–1.50 (m,1H), 1.52–1.60 (m, 1H), 1.76–1.85 (m, 2H), 1.90–2.05 (m, 1H),2.50–2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82–3.88 (m, 1H)ppm. MS (DCl/NH₃): m/z 128 (M+H)⁺.

Reference Example 2 (S)-3-quinuclidinol Reference Example 2A(R)-1-Azabicyclo[2.2.2]oct-3-yl Benzoate (L) Tartrate

1-Azabicyclo[2.2.2]oct-3-yl benzoate (Sigma, 17.9 g, 77.5 mmol) wastreated with (L)-tartaric acid (Aldrich, 99% ee, 11.63 g, 77.5 mmol) inethanol (80%, 222 mL) at ambient temperature for 1 week. The white solidwas filtered off and dried under reduced pressure to provide 6.5 g ofthe title compound with ˜80% enantiomeric excess. Recrystallization fromethanol provided an enantiomeric excess of >98%. HPLC: chiralpak ADcolumn 25 cm×4 mm ID; ethanol:hexanes 15:85; flow rate 1 mL/minute; uv220 nM; Retention time 13.3 minutes. MS (DCl/NH₃) m/z 232 (M+H)⁺.

Reference Example 2B (R)-quinuclidin-3-ol

The product of Reference Example 2A (4.5 g, 11.8 mmol) in MeOH (40 mL)was treated with 15% aqueous NaOH (40 mL) and heated at 50 ° C. for 10hours. The mixture was allowed to cool to room temperature, the MeOH wasremoved under reduced pressure, and the residue was extracted withchloroform (4×80 mL). The extracts were combined, dried over MgSO₄(anhydrous), filtered, and the filtrate was concentrated to give thetitle product as a white solid (1.35 g, yield, 90%). MS (DCl/NH₃) m/z128 (M+H)⁺.

Reference Example 2C (S)-1-azabicyclo[2.2.2]oct-3-yl Benzoate(D)-Tartrate

The mother liquors of Reference Example 2A were concentrated underreduced pressure, treated with aqueous NaOH (1 N, 50 mL) at roomtemperature, stirred for 30 minutes, and extracted with chloroform(3×100 mL). The extracts were combined, dried (MgSO₄), filtered, and thefiltrate was concentrated under reduced pressure. The residue (15.25 g,66 mmol) was treated with (D)-tartaric acid (Aldrich, 97% ee, 9.9 g, 66mmol,) in ethanol (80%, 190 ml) at room temperature and stirred for 3days. The mixture was filtered to provide the title product, 92.3%enantiomeric excess (7.0 g, 28% yield). (HPLC: chiralpak AD column 25cm×4 mm ID; ethanol:hexanes 15:85; flow rate 1 mL/minute; uv 220 nm;Retention time 7.87 minutes).

Reference Example 2D (S)-quinuclidin-3-ol

The product of Reference Example 2C (7.0 g, 18.4 mmol) was treated withNaOH (aqueous) according to the procedure of Example 1 B. The titleproduct was obtained as a white solid (2.0 g, yield, 86%). MS (DCl/NH₃)m/z 128 (M+H)⁺.

EXAMPLES Example 1 3-(3-phenoxyphenoxy)quinuclidine hydrochlorideExample 1A 3-(3-phenoxyphenoxy)quinuclidine

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran(anhydrous, 10 mL) was treated with 3-phenoxyphenol (Aldrich, 186 mg, 1mmol), DIAD (diisopropyl azadicarboxylate, Aldrich, 404 mg, 2 mmol), andtriphenylphosphine (Aldrich, 522 mg, 2 mmol) at ambient temperature fortwo days. The reaction mixture was concentrated under reduced pressure.The residue was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O,90:10:1, R_(f). 0.30) as oil (250 mg, yield, 85%). ¹H NMR (MeOH-d₄, 300MHz) δ 1.42–1.58 (m, 1H), 1.64–1.75 (m, 1H), 1.78–1.88 (m, 1H),2.00–2.15 (m, 1H), 2.16–2.24 (m, 1H), 2.80–3.1 3.34–3.40 (m, 1H), 4.52(m, 1H), 6.52 (m, 2H), 6.67(dd, J=2.4, 1.0 Hz, 1H), 6 2H), 7.11 (tt,J=7.5, 1.7 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.35 (m, 2H) ppm. MS(DCl/NH₃) m/z 296 (M+H)⁺.

Example 1B 3-(3-phenoxyphenoxy)quinuclidine hydrochloride

The product of 1A (250 mg, 0.85 mmol) in ethyl acetate (5 mL) wastreated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) to provide titlecompound as a solid (165 mg, 59% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ1.72–2.20 (m, 3H), 2.25–2.34 (m, 1H), 2.50 (m, 1H), 3.30–3.45 (m, 5H),3.78 (m, 1H), 4.90 (m, 1H), 6.60(m, 6.72 (ddd, J=8.1, 2.3, 0.7 Hz, 1H),6.99 (m, 1H), 7.13 (tt, J=7.1, 1.0 Hz, 1H), 7.25–7.39(m, 3H) ppm. MS(DCl/NH₃) m/z 296(M+H)⁺. Anal. calculated for C₁₉H₂₁NO₂.1.0HCl.0.3H₂O:C, 67.67; H, 6.75; N, 4.15. Found: C, 67.56; H, 6.45 4.26.

Example 2 3-(4-phenoxyphenoxy)quinuclidine hydrochloride Example 2A3-(4-phenoxyphenoxy)quinuclidine

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with1-iodo-4-phenoxy-benzene (Aldrich, 296 mg, 1 mmol), Cul (StremChemicals, 19 mg, 0.1 mmol), 1,10-phenanthroline (Aldrich, 36 mg, 0.2mmol), and Cs₂CO₃ (660 mg, 2.0 mmol) in toluene (anhydrous, Aldrich, 10mL) and heated at 110° C. for two days. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate (50 mL)and washed with water (2×10 mL). The organic phase was concentrated andthe title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃H₂O, 90:10:1, R_(f). 0.20) as oil (220 mg, yield, 75%).¹H NMR (MeOH-d₄, 300 MHz) δ 1.45–1.58 (m, 1H), 1.64–1.85 (m, 2H),2.00–2.15 (m, 1H), 2.20–2.30 (m, 2.70–3.10 (m, 5H), 3.34–3.40 (m, 1H),4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt, J=7.5, 1.0 Hz, 1H), 7.20–7.41(m, 2H) ppm. MS (DCl/NH₃) m/z 296 (M+H)⁺.

Example 2B 3-(4-phenoxyphenoxy)quinuclidine hydrochloride

The product of 2A (220 mg, 0.75 mmol) in ethyl acetate (5 mL) wastreated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) to provide the titlecompound as a solid (171 mg, yield, 69%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.80–2.20 (m, 3H), 2.30–2.40 (m, 1H), 2.50 (m, 1H), 3.30–3.45 (m, 5H),3.76 (m, 1H), 4.90 (m, 1H), 6.90-6H), 7.05–7.09(m, 1H) 7.20–7.42 (m, 2H)ppm. MS (DCl/NH₃) m/z 296(M+H)⁺. An calculated for C₁₉H₂₁NO₂.1.0HCl: C,68.77; H, 6.68; N, 4.22. Found: C, 68.56; H, 6.45; N, 4.26.

Example 3 (R)-3-(4-phenoxyphenoxy)quinuclidine hydrochloride Example 3A(R)-3-(4-phenoxyphenoxy)quinuclidine

3-(R)-Hydroxy-quinuclidine (the product of Reference Example 1, 152 mg,1.2 mmol), was coupled with 1-iodo-4-phenoxy-benzene (178 mg, 0.6 mmol)according to the procedure of Example 3A. The title product was purifiedby chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) asoil (25 mg, yield, 14%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.45–1.58 (m, 1H),1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 1H), 2.70–3.10 (m,5H), 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt,J=7.5, 1.0 Hz, 1H), 7.30 (t, J=7.5 Hz, 2H) ppm. MS (DC m/z 296 (M+H)⁺.

Example 3B (R)-3-(4-phenoxyphenoxy)quinuclidine hydrochloride

The product of Example 3A (20 mg, 0.07 mmol) in ethyl acetate (4 mL) wastreated with 4M HCl in 1,4-dioxane (0.5 mL) to provide the titlecompound as a solid (20 mg, yield, 90%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.80–2.20 (m, 3H), 2.30–2.40 (m, 1H), 2.50 (m, 1H), 3.30–3.45 (m, 5H),3.76 (m, 1H), 4.90 (m, 1H), 6.90–6H), 7.05–7.09 (m, 1H) 7.20–7.42 (m,2H) ppm. MS (DCl/NH₃) m/z 296(M+H)⁺. A calculated forC₁₉H₂₁NO₂.1.0HCl.0.4H₂O: C, 67.31; H, 6.78; N, 4.13. Found: C, 67.03; H,6.41; N, 3.93.

Example 4 (S)-3-(4-phenoxyphenoxy)quinuclidine hydrochloride Example 4A(S)-3-(4-phenoxyphenoxy)quinuclidine

3-(R)-Hydroxy-quinuclidine (the product of Reference Example 1, 152 mg,1.2 mmol), was treated with 1-iodo-4-phenoxy-benzene (178 mg, 0.6 mmol)according to the procedure of Example 3A to provide the title compound.(80 mg, yield, 45.2%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.45–1.58 (m, 1H),1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 1H), 2.70–3.10 (m,5H), 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt,J=7.5, 1.0 Hz, 1H), 7.30 (t, J=7.5 Hz, 2H) ppm. MS (D m/z 296 (M+H)⁺.

Example 4B (S)-3-(4-phenoxyphenoxy)quinuclidine hydrochloride

The product of Example 4A (80 mg, 0.27 mmol) in ethyl acetate (4 mL) wastreated with 4M HCl in 1,4-dioxane (0.5 mL) to provide the titlecompound as solid (57 mg, yield, 63%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.80–2.20 (m, 3H), 2.30–2.40 (m, 1H), 2.50 (m, 1H), 3.30–3.45 (m, 5H),3.76 (m, 1H), 4.90 (m, 1H), 6.90–6H), 7.05–7.09 (m, 1H) 7.20–7.42 (m,2H) ppm. MS (DCl/NH₃) m/z 296(M+H)⁺. A calculated for C₁₉H₂₁NO₂. 1.0HCl:C, 68.77; H, 6.68; N, 4.22. Found: C, 68.50; H, 6.69; N, 4.12.

Example 5 3-{4-[4-(trifluoromethyl)phenoxy]phenoxy}quinuclidinehydrochloride Example 5A3-{4-[4-(trifluoromethyl)phenoxy]phenoxy}quinuclidine

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with4-(4-trifluoromethyl-phenoxy)-phenol (Aldrich, 255 mg, 1 mmol) accordingto the procedure of Example 1A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.50) as oil(180 mg, yield, 49%). ^(H NMR (MeOH-d) ₄, 300 MHz) δ 1.50–1.58 (m, 1H),1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 1H), 2.76–3.10 (m,5H), 3.38–3.50 (m, 1H), 4.60 (m, 1H), 6.96–7.04 (m, 6H), 7.60 (d, J=8.5Hz, 2H) ppm. MS (DCl/NH₃) m/z 364 (M+H)⁺.

Example 5B 3-{4-[4-(trifluoromethyl)phenoxy]phenoxy}quinuclidinehydrochloride

The product of 5A (180 mg, 0.49 mmol) in ethyl acetate (5 mL) wastreated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) to provide the titlecompound as a solid (110 mg, yield, 56%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.80–2.28 (m, 3H), 2.35–2.40 (m, 1H), 2.56 (m, 1H), 3.30–3.45 (m, 5H),3.80 (m, 1H), 4.94 (m, 1H), 7.02–7.10 (m, 6H), 7.60 (d, J=8.4 Hz, 2H)ppm. MS (DCl/NH₃) m/z 364(M+H)⁺. Anal. calculated forC₂₀H₂₀F₃NO₂.1.0HCl.0.5H₂O: C, 58.76; H, 5.42; N, 3.43. Found: C, 58.54;H, N, 3.35.

Example 6 3-[4-(4-fluorophenoxy)phenoxy]quinuclidine hydrochlorideExample 6A 3-[4-(4-fluorophenoxy)phenoxy]quinuclidine

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with4-(4-fluoro-phenoxy)-phenol (Aldrich, 205 mg, 1 mmol) according to theprocedure of Example 1A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.45) as oil(230 mg, yield, 73%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.52 (m, 1H),1.64–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.66–3.00 (m,5H), 3.30–3.40 (m, 1H), 4.48(m, 1H), 6.61 (dt, J=10.5, 2.4 Hz, 1H),6.71(dd, J=8.1, 2.3 Hz, 1H), 6.76 (tdd, J=8.4, 2.3, 1.0 Hz, 1H),6.87–7.00 (m, 3H), 7.22–7.32 (m, 2H) ppm. MS (DCl/NH₃) m/z 314 (M+H)⁺.

Example 6B 3-[4-(4-fluorophenoxy)phenoxy]quinuclidine hydrochloride

The product of Example 6A (230 mg, 0.73 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) to provide thetitle compound as a solid (106 mg, yield, 42%). ¹H NMR (MeOH-d₄, 300MHz) δ 1.79–2.21 (m, 3H), 30 2.32–2.40 (m, 1H), 2.56 (m, 1H), 3.30–3.48(m, 5H), 3.80 (m, 1H), 4.90 (m, 6.62(dt, J=10.5, 2.4 Hz, 1H), 6.73(dd,J=8.1, 2.3Hz, 1H), 6.78 (tdd, J=8.5, 2.3, 1.0 Hz, 1H), 7.03 (s, 4H),7.30 (td, J=8.2, 6.7Hz, 1H) ppm. MS (DCl/NH₃) m/z 314 (M+H)⁺. Anal.calculated for C₁₉H₂₀FNO₂.1.0HCl: C, 65.23; H, 6.05; N, 4.00. Found: C,64.96; H, 6.17; N, 3.96.

Example 7 4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenoxy]phenolhydrochloride Example 7A4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenoxy]phenol

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with4,4′-dihydroxydiphenyl ether (TCl, 202 mg, 1 mmol) according to theprocedure of Example 1A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃ H₂O, 90:10:1, R_(f). 0.2) as oil(210 mg, yield, 68%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.55 (m, 1H),1.60–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.75–2.98 (m,5H), 3.20–3.30 (m, 1H), 4.45(m, 1H), 6.62–6.96 (m, 8(DCl/NH₃) m/z 312(M+H)⁺.

Example 7B 4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenoxy]phenolhydrochloride

The product of Example 7A (210 mg, 0.68 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) to provide thetitle compound as a solid (140 mg, yield, 59%). ¹H NMR (MeOH-d₄, 300MHz) δ 1.73–2.19 (m, 3H), 2.21–2.40 (m, 1H), 2.41–2.56 (m, 1H),3.30–3.50 (m, 5H), 3.69–3.83 (m, 1H), 4.80 (m, 1H), 6.59–7.04 (m, 8H)ppm. MS (DCl/NH₃) m/z 312 (M+H)⁺. Anal. calculated for C₁₉H₂₁NO₃.1.0HCl:C, 65.61; H, 6.37; N, 4.03. Found: C, 65.31; H, 6.32; N, 3.86.

Example 8 4,4′-di (1-aza-bicyclo[2.2.2]oct-3-yloxy)-diphenyl etherbis(hydrochloride)

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with4,4′-dihydroxydiphenyl ether (TCl, 202 mg, 1 mmol) according to theprocedure of Example 7A. The free base of title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃ H₂O, 90:10:1, R_(f). 0.4) as oil(60 mg, yield, 7%). It was then treated with HCl (Aldrich, 4 M indioxane, 0.25 mL, 1 mmol) in EtOAc (5 mL) at ambient temperature for 1hour to give the title compound as solid (40 mg, yield, 59%) ¹H NMR(MeOH-d₄, 300 MHz) δ 1.78–2.21 (m, 3H), 2.21–2.39 (m, 1H), 2.39–2.62 (m,1H), 3.29–3.49 (m, 5H), 3.79 (dd, J=13.7, 8.6 Hz, 1H), 4.73–4.93 (m,1H), 6.78–7.10 (m, 4H) ppm. MS (DCl/NH₃) m/z 421 (M+H)⁺.

Example 9 4-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenoxy}phenolfumarate Example 9A4-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenoxy}phenol

3-(S)-Hydroxy-quinuclidine (the product of Reference Example 2D, 127 mg,1 mmol) was treated with 4,4′-dihydroxydiphenyl ether (TCl, 202 mg, 1mmol) according to the procedure of Example 1A. The title compound waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f).0.2) as oil (48 mg, yield, 15%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.55(m, 1H), 1.60–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H),2.75–2.98 (m, 5H), 3.20–3.30 (m, 1H), 4.45 (m, 1H), 6.62–6.96 (m, 8H)ppm. MS (DCl/NH₃) m/z 312 (M+H)⁺.

Example 9B 4-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenoxy}phenolfumarate

The product of Example 9A (48 mg, 0.15 mmol) in ethyl acetate:MeOH (3mL, 10:1) was treated with fumaric acid (Aldrich, 17.4 mg, 0.15 mmol) atroom temperature and stirred overnight to provide the title compound asa solid (34 mg, yield, 62%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.73–2.19 (m,3H), 2.21–2.40 (m, 1H), 2.41–2.56 (m, 1H), 3.03–3.27 (m, 5H), 3.59–3.73(m, 1H), 4.67 (m, 1H), 6.67 (s, 1H), 6.67–6.98 (m, 8H) ppm. MS (DCl/NH₃)m/z 312 (M+H)⁺. Anal. Calculated for C₁₉H₂₁NO₃.0.5C₄H₄O₄. 0.35H₂O C,67.13; H, 6.36; N, 3.73. Found: C, 67.04; H, 6.46; N, 3.75.

Example 10 4-{[4-(1-azabicyclo[2.2.21]oct-3-yloxy)phenyl]thio}phenolhydrochloride Example 10A4-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]thio}phenol

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with4,4′-dihydroxydiphenyl thioether (TCl, 218 mg, 1 mmol) according to theprocedure of Example 1A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.2) as oil(280 mg, yield, 86%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.50 (m, 1H),1.55–1.87 (m, 2H), 1.90–2.15 (m, 2H), 2.70-5H), 3.20–3.30 (m, 1H),4.46(m, 1H), 6.74 (d, J=8.9 Hz, 2H), 6.83 (d, J=9. 7.17 (d, J=8.8 Hz,2H), 7.19 (d, J=8.8 Hz, 2H) ppm. MS (DCl/NH₃) m/z 328 (M+H)⁺

Example 10B 4-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]thio}phenolhydrochloride

The product of Example 10A (200 mg, 0.61 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) to provide thetitle compound as a solid (140 mg, yield, 63%). ¹H NMR (MeOH-d₄, 300MHz) δ 1.75–2.19 (m, 3H), 2.19–2.38 (m, 1H), 2.43–2.56 (m, 1H),3.20–3.50 (m, 5H), 3.66–3.84 (m, 1H), 6.76 (d, J=8.9 Hz, 2H), 6.90 (d,J=8.9 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H) ppm. MS(DCl/NH₃) m/z 328 (M+H)⁺. Anal. calculated for C₁₉H₂₁NO₂S.1.0HCl.0.8H₂O:C, 60.32; H, 6.29; N, 3.70. Found: C, 60.34; H, 6.N, 3.32.

Example 11 4-({4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}thio)phenolfumarate Example 11A4-({4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}thio)phenol

3-(S)-Hydroxy-quinuclidine (the product of Reference Example 2D, 127 mg,1 mmol) was treated with 4,4′-dihydroxydiphenyl thioether (TCl, 202 mg,1 mmol) according to the procedure of Example 1A. The title compound waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f).0.2) as oil (38 mg, yield, 12%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.50(m, 1H), 1.55–1.87 (m, 2H), 1.90–2.15 (m, 2H), 2.70–2.98 (m, 5H),3.20–3.30 (m, 1H), 4.47(m, 1H), 6.74 Hz, 2H), 6.83 (d, J=9.1 Hz, 2H),7.15–7.20 (m, 4H) ppm. MS (DCl/NH₃) m/z 328 (M+H)⁺.

Example 11B4-({4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}thio)phenol fumarate

The product of Example 11A (38 mg, 0.12 mmol) in ethyl acetate:MeOH (5mL, 10:1) was treated with fumaric acid 17.4 mg (0.15 mmol) at roomtemperature overnight. The title compound was obtained as a solid (30mg, yield, 66%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.75–2.19 (m, 3H),2.19–2.38 (m, 1H), 2.33–2.46 (m, 1 3.03–3.27 (m, 5H), 3.50–3.64 (m, 1H),4.70 (m, 1H), 6.67 (s, 1H), 6.76 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.9 Hz,2H), 7.15–7.26 (m, 4H) ppm. MS (DCl/NH₃) m/z 328 (M+H)⁺. Anal.Calculated for C₁₉H₂₁NO₂S.0.5C₄H₄O₄.0.4H₂O C, 64.23; H 6.11; N, 3.57.Found: C, 64.14; H, 5.83; N, 3.49.

Example 12 4,4′-di[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-diphenylthioether tri(hydrochloride) Example 12A4,4′-di[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-diphenyl thioether

3-(S)-Hydroxy-quinuclidine (the product of Reference Example 2D, 508 mg,4.0 mmol) was treated with 4,4′-dihydroxydiphenyl thioether (TCl, 872mg, 4.0 mmol) according to the procedure of Example 11A. The titlecompound the was purified via column chromatography (SiO₂,CH₂Cl₂/MeOH(v.2% NH₃.H₂O), 90/10, 10% Rf=0.08) (110 mg, yield, 6%).¹H NMR (MeOH-d₄,300 MHz) 1.37–1.88 (m, 6H), 1.90–2.06 (m, 2H), 2.08–2.18 (m, 2H),2.64–3.00 (m, 10H), 3.08–3.18 (m, 4.45–4.52 (m, 2H), 6.85 (d, J=8.8 Hz,4H), 7.24 (d, J=8.8 Hz, 4H) ppm. MS (DCl/N m/z 437 (M+H)⁺.

Example 12B 4,4′-di[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-diphenylthioether tri(hydrochloride)

The product of Example 12A (110 mg, 0.25 mmol) was treated with HCl(Aldrich, 4 M in dioxane, 0.5 mL, 2 mmol) in EtOAc (5 mL) at ambienttemperature for 16 hours to give the title compound (53.3 mg, 39%). ¹HNMR (MeOH-d₄, 300 MHz) 1.80–2.17 (m, 6H), 2.22–2.35 (m, 2H), 2.45–2.53(m, 2H), 3.25–3.45 (m 10H), 3.80 (dd, J=13.7, 8.3 Hz, 2H), 4.84–4.91 (m,2H), 6.95 (d, J=8.8 Hz, 4H), 7.29 (d, J=8.8 Hz, 4H) ppm. MS (DCl/NH₃)m/z 437 (M+H)⁺. Anal. Calculated for C₂₆H₃₂N₂O₂S.3.0 HCl: C, 57.20; H,6.46; N, 5.13. Found: C, 57.35; H, 6.42; N, 4.97.

Example 13 3-{4-[(4-isopropoxyphenyl)thio]phenoxy}quinuclidine fumarateExample 13A 3-{4-[(4-isopropoxyphenyl)thio]phenoxy}quinuclidine

The product of Example 10A (80 mg, 0.24 mmol) was treated with isopropylalcohol (60 mg, 1 mmol) according to the procedure of Example 1A. Thetitle compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.5) as oil (80 mg, yield, 90%). ¹HNMR (MeOH-d₄, 300 MHz) δ 1.30 (d, J=6.1 Hz, 6H), 1.60–2.10 (m, 3H),2.15–2.25 (m, 1H), 2.30–2.40 (m, 2H), 2,98–3.20 (m, 6H), 3.50–3.60 (m,1H), 4.50–4.58(m, 1H), 7.70–4.78 (m, 1H), 6.87 (t, J =9.2 Hz), 4H), 7.23(d, J=8.8 Hz, 2H), 7.24 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH₃) m/z 370(M+H)⁺.

Example 13B 3-{4-[(4-isopropoxyphenyl)thio]phenoxy}quinuclidine fumarate

The product of Example 13A (74 mg, 0.2 mmol) in ethyl acetate:MeOH (5mL, 10:1) was treated with fumaric acid (Aldrich, 21 mg, 0.2 mmol). Thetitle compound was obtained as solid (90 mg, yield, 95%): ¹H NMR(MeOH-d₄, 300 MHz) δ 1.75–2.19 (m, 3H), 2.19–2.38 (m, 1H), 2.43–2.56 (m,1H), 3.20–3.50 (m, 5H), 3.66–3.84 (m, 1H), 4.80 (m, 1H), 6.76 (d, J=8.9Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8Hz, 2H) ppm. MS (DCl/NH₃) m/z 70 (M+H)⁺. Anal. Calculated forC₂₂H₂₇NO₂S.1.0C₄H₄O₄.0.4H₂O: C, 63.37; H, 6.50; N, 2.84 63.57; H, 6.20;N, 2.80.

Example 14 3-[4-(pyridin-3-yloxy)phenoxy]quinuclidine hydrochlorideExample 14A 3-(4-iodophenoxy)quinuclidine

3-Hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol) in toluene (anhydrous,Aldrich, 50 mL) was treated with 1,4-diiodobenzene (Aldrich, 7.9 g, 24mmol), Cul (Strem Chemicals, 0.38 g, 2 mmol), 1,10-phenanthroline(Aldrich, 0.72 g, 4 mmol), and Cs₂CO₃ (Aldrich, 8.15 g, 25 mmol), heatedat 110° C. for 40 hours. The reaction mixture was allowed to cool toroom temperature, diluted with chloroform (100 mL), and washed withwater (2×10 mL). The organic phase was concentrated and the titlecompound was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O,90:10:1, R_(f). 0.20) as oil (3.7 g, yield, 56%). ¹H NMR (MeOH-d₄, 300MHz) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H),2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H),6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCl/NH₃) m/z330 (M+H)⁺.

Example 14B 3-(4-iodophenoxy)quinuclidine hydrochloride

The product of Example 14A (3.7 g, 11.2 mmol) in ethyl acetate (50 mL)was treated with 4M HCl in 1,4-dioxane (5 mL, 20 mmol). The titlecompound was obtained as a solid (4.0 g, yield, 98%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.80–2.20 (m, 3H), 2.30–2.40 (m, 1H), 2.50 (m, 1H), 3.30–3.48(m, 5H), 3.76 (m, 1H), 4.92 (m, 1H), 6.80 (d, J=9.1 Hz, 2H), 7.61 (d,J=8.8 Hz, 2H) ppm. MS (DCl/NH₃) m/z 330 (M+H)⁺. Anal. calculated forC₁₃H₁₆INO.1.0HCl: C, 42.70; H, 4.69; N, 3.83. Found: C, 42.72; H, 4.61;N, 3.65.

Example 14C 3-[4-(Pyridin-3-yloxy)phenoxy]quinuclidine hydrochloride

The product of Example 14B (365 mg, 1.0 mmol) inN-methylpyrrolidin-2-one (2 mL) was treated with 3-hydroxypyridine(Aldrich, 190 mg, 2.0 mmol), CuCl (Strem Chemicals, 45 mg, 0.5 mmol),2,2,6,6-tetramethyl-heptane-3,5-dione (Strem Chemicals, 37 mg, 0.2mmol), Cs₂CO₃ (Strem Chemicals, 650 mg, 2 mmol) and heated at 160° C.for 6 hours. The mixture was allowed to cool to room temperature,diluted with CH₂Cl₂ (5 mL), filtered, and the filtrate was directlypurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f).0.20) to provide the title compound as an oil (230 mg, yield, 78%). Thetitle compound in ethyl acetate (5 mL) was treated with 4M HCl in1,4-dioxane (0.5 mL, 2 mmol) to provide the dihydrochloride salt as asolid (210 mg, yield, 74%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.80–2.22 (m,3H), 2.30–2.40 (m, 1H), 2.55–2.65 (m, 1H), 3.30–3.46 (m, 5H), 3.76–3.86(m, 1H), 4.96 (m, 1H), 7.15 (d, J=9.2 Hz, 2H), 7.22 (d, J=9.1 Hz, 2H)8.00(dd, J=8.5, 5.1 Hz, 1H), 8.13 (ddd, J=8.8, 2.7, 1.0 Hz, 1H), 8.55(d, J=5.4 Hz, 1H), 8.59 (d, J=2.7 Hz, 1H) ppm. MS (DCl/NH₃) m/z 297(M+H)⁺. Anal. Calculated for C₁₈H₂₀N₂O₂.2.0HCl: C, 58.54; H, 6.00; N,7.59. Found: C, 58.18; H, 6.13; N, 7.31.

Example 15 3-[4-(thien-3-yloxy)phenoxy]quinuclidine hydrochlorideExample 15A 3-[4-(benzyloxy)phenoxy]quinuclidine

3-Hydroxy quinuclidine (Aldrich, 2.54 9, 20 mmol) was treated with1-benzyloxy-4-iodo-benzene (Aldrich, 3.10 g, 10 mmol) according to theprocedure of Example 14A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.40) as anoil (1.30 g, yield, 42%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.45–1.56 (m, 1H),1.64–1.80 (m, 2H), 2.00–2.10 (m, 1H), 2.15–2.24 (m, 1H), 2.76–3.10 (m,5H), 3.40–3.46 (m, 1H), 4.48 (m, 1H), 5.10 (s, 2H), 6.73–6.96 (m 4H),7.20–7.40 (m, 5H) ppm. MS (DCl/NH₃) m/z 310 (M+H)⁺.

Example 15B 3-[4-(benzyloxy)phenoxy]quinuclidine hydrochloride

The product of Example 15A (100 mg, 0.32 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2.0 mmol). The titlecompound was obtained as a solid (80 mg, yield, 72%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.80–2.16 (m, 3H), 2.25–2.40 (m, 1H), 2.46 (m, 1H), 3.30–3.46(m, 5H), 3.76 (m, 1H), 4.75 (m, 1H), 5.02 (s, 2H), 6.80–6.95 (m, 4H),7.28–7.40 (m, 5H) ppm. MS (DCl/NH₃) m/z 310 (M+H)⁺. Anal. calculated forC₂₀H₂₃NO₂.1.4HCl.0.8H₂O: C, 64.08; H, 6.99; N, 3. 74. Found: C, 64.14;H, 6.52; N, 3.86.

Example 15C 4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenol

The product of Example 15A (1.20 g, 3.9 mmol) in ethanol (20 mL) wastreated with Pd/C (Aldrich, 10% wt., 0.2 g) under H₂ at ambienttemperature for 10 hours. The mixture filtered through a short column ofdiatomaceous earth and the filtrate was concentrated under reducedpressure to provide the title compound as a colorless oil (0.72, yield,84%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.56 (m, 1H), 1.64–1.75 (m, 1H),1.80–1.92 (m, 1H), 2.00–2.30 (m, 2H), 2.76–3.02 (m, 5H), 3.25–3.35 (m,1H), 4.40 (m, 1H), 6.60–6.80 (m, 4H) ppm. MS (DCl/NH₃) m/z 220 (M+H) ⁺.

Example 15D 4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenol hydrochloride

The product of Example 15C (66 mg, 0.3 mmol) in ethyl acetate (4 mL) wastreated with 4M HCl in 1,4-dioxane (0.2 mL, 0.8 mmol). The titlecompound was obtained as a solid (80 mg, yield, 92%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.80–2.10 (m, 3H), 2.25–2.40 (m, 1H), 2.46 (m, 1H), 3.30–3.46(m, 5H), 3.68 (m, 1H), 4.70 (m, 1H), 6.72 (dt, J=9.1, 2.4 Hz, 2H), 6.82(dt, J=9.2, 2.7 Hz, 2H) ppm. MS (DCl/NH₃) m/z 220 (M+H)⁺. Anal.Calculated for C₁₃H₁₇NO₂.1.0HCl.0.1H₂O: C, 60.63; H, 7.12; N, 5.44.Found: C, 60.66; H, 7.10; N, 5.28.

Example 15E 3-[4-(thien-3-yloxy)phenoxy]quinuclidine

The product of Example 15C (110 mg, 0.5 mmol) inN-methylpyrrolidin-2-one (2 mL) was treated with 3-iodothiophene(Aldrich, 209 mg, 1 mmol) according to the procedure of Example 14C. Thetitle compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.30) as oil (40 mg, yield, 26%).¹H NMR (MeOH-d₄, 300 MHz) δ 1.50–1.60 (m, 1H), 1.64–1.92 (m, 2H),2.06–2.15 (m, 1H), 2.20–2.28 (m, 1H), 2.80–3.10 (m, 5H), 3.40–3.46 (m,1H), 4.55 (m, 1H), 6.51 (dd, J=3.4, 1.4 Hz, 1H), 6.80 (dd, J=5.2, 1.5Hz, 1H), 6.91 (dt, J=9.4, 2.7 Hz, 2H), 6.99 (dt, J=9.2, 2.8 Hz, 2H),7.33 (dd, J=5.4, 3.1 Hz, 1H) ppm. MS (DCl/NH₃) m/z 302 (M+H)⁺.

Example 15F 3-[4-(thien-3-yloxy)phenoxy]quinuclidine hydrochloride

The product of Example 15E (40 mg, 0.13 mmol) in ethyl acetate (4 mL)was treated with 4M HCl in 1,4-dioxane (0.2 mL, 0.8 mmol). The titlecompound was obtained as a solid (26 mg, yield, 59%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.80–2.10 (m, 3H), 2.25–2.46 (m, 1H), 2.56 (m, 1H), 3.30–3.50(m, 5H), 3.80 (m, 1H), 4.85 (m, 1H), 6.55 (dd, J=3.4, 1.7 Hz, 1H), 6.81(dd, J=5.5, 1.7 Hz, 1H), 6.97 (dt, J=9.5, 3.0 Hz, 2H), 7.02 (dt, J=9.5,3.1 Hz, 2H), 7.34 (dd, J=5.1, 3.1 Hz, 1H) ppm. MS (DCl/NH₃) m/z 302(M+H)⁺. Anal. Calculated for C₁₇H₁₉NO₂S.1.0HCl.0.5H₂O: C, 58.86; H,6.10; N, 4.04. Found: C, 59.08; H, 5.88; N, 4.06.

Example 16 3-{4-[(5-bromopyrimidin-2-yl)oxy]phenoxy}quinuclidinetrifluroacetate Example 16A3-{4-[(5-bromopyrimidin-2-yl)oxy]phenoxy}quinuclidine

The product of Example 15C (110 mg, 0.5 mmol) in tetrahydrofuran (5 mL)was treated with potassium tert-butoxide (Aldrich, 1M in THF, 0.6 mL,0.6 mmol) at ambient temperature for 5 minutes followed by addition of5-bromo-2-iodo-pyrimidine (Aldrich, 142 mg, 0.5 mmol) and stirred at 60°C. for 10 hours. The reaction mixture was allowed to cool to roomtemperature, diluted with ethyl acetate (20 mL), and washed with brine(2×5 mL). The organic phase was concentrated under reduced pressure andthe title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.40) as oil (100 mg, yield, 53%).¹H NMR (MeOH-d₄, 300 MHz) δ 1.50–1.60 (m, 1H), 1.64–1.92 (m, 2H),2.06–2.15 (m, 1H), 2.20–2.28 (m, 1H), 2.80–3.10 (m, 5H), 3.40–3.46 (m,1H), 4.55 (m, 1H), 7.30–7.45 (m, 2H), 7.52–7.60(m, 2H), 7.70–7.82(m, 2H)ppm. MS (DCl/NH₃) m/z 376 (M+H)⁺, 378 (M+H) ⁺.

Example 16B 3-{4-[(5-bromopyrimidin-2-yl)oxy]phenoxy}quinuclidinetrifluroacetate

The product of Example 16A (100 mg, 0.26 mmol) in ethyl acetate (4 mL)was treated with trifluroacetic acid (113 mg, 1 mmol). The titlecompound was obtained as solid (100 mg, yield, 64%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.85–2.16 (m, 3H), 2.25–2.46 (m, 1H), 2.56 (m, 1H), 3.30–3.53(m, 5H), 3.80 (m, 1H), 4.95 (m, 1H), 7.04 (dt, J=9.1, 2.4 Hz, 2H), 7.14(dt, J=9.1, 2.3 Hz, 2H), 8.60 (s, 2H) ppm. MS (DCl/NH₃) m/z. m/z 376(M+H)⁺, 378 (M+H)⁺. Anal. Calculated for C₁₇H₁₈BrN₃O₂.2.0CF₃CO₂H.2.0H₂O:C, 39.39; H, 3.78; N, 6.56. Found: C, 39.19; H, 3.78; N, 6.83.

Example 17 N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-phenylaminehydrochloride Example 17AN-[4-(1-azabicyclo[2.2.21]oct-3-yloxy)phenyl]-N-phenylamine

The product of Example 14B (370 mg, 1.0 mmol) in toluene (10 mL) wastreated with aniline (Aldrich, 140 mg, 1.5 mmol), Pd₂(dba)₃ (StremChemicals, 18.3 mg, 0.02 mmol),1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride, 95%, 26.9 mg, 0.06mmol), sodium tert-butoxide (Aldrich, 144 mg, 1.5 mmol) and heated at110° C. for 15 hours. The reaction mxiture was was diluted with ethylacetate (20 mL) and washed with brine (2×5 mL). The organic phase wasconcentrated and the title compound was purified by chromatography(SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) as oil (160 mg, yield,53%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.53 (m, 1H), 1.62–1.85 (m, 2H),1.93–2.20 (m, 2H), 2.80–2.94 (m, 5H), 3.18–3.25 (m, 1H), 4.38–4.46 (m,1H), 6.73 (tt, J=7.5, 3.0 Hz, 1H), 6.82 (dt, J=9.1, 3.4 Hz, 2H),6.91–6.96 (m, 2H), 7.02 (dt, J=9.1, 2.4 Hz, 2H), 7.11–7.18 (m, 2H) ppm.MS (DCl/NH₃) m/z 295 (M+H)⁺.

Example 17B [N-[4-(1-azabicyclo[2.2.21]oct-3-yloxy)phenyl]-N-phenylaminehydrochloride

The product of Example 17A (160 mg, 0.53 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The titlecompound was obtained as a solid (150 mg, yield, 64%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.85–2.20 (m, 3H), 2.30–2.42 (m, 1H), 2.45–2.52 (m, 1H),3.30–3.45 (m, 5H), 3.70–80(m, 1H), 4.80 (m, 1H), 6.78 (tt, J=7.5, 3.0Hz, 1H), 6.90 (dt, J=8.8, 3.4 Hz, 2H), 6.94–699 (m, 2H), 7.07 (dt,J=8.8, 3.3 Hz, 2H), 7.12–7.20 (m, 2H) ppm. MS (DCl/NH₃) m/z 295 (M+H)⁺.Anal. Calculated for C₁₉H₂₂N₂O.2.0HCl.0.4H₂O: C, 67.50; H, 7.10; N,8.29. Found: C, 67.34; H, 6.82; N, 8.03.

Example 18N-{4-[(3R)-1-azabicyclo[2.2.21]oct-3-yloxy]phenyl}-N-phenylaminehydrochloride Example 18A (3R)-3-(4-iodophenoxy)quinuclidine

3-(R)-Hydroxyquinuclidine (the product of Reference Example 1, 0.64 g,5.0 mmol) was treated with 1,4-diiodobenzene (1.98 g, 6.0 mmol)according to the procedure of Example 14A. The title compound waspurified by flash chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1,R_(f). 0.30) as a solid (0.50 g, yield, 15%). ¹H NMR (MeOH-d₄, 300 MHz)δ 1.41–1.54 (m, 1H), 1.59–1.73 (m, 1H), 1.73–1.86 (m, 1H), 1.92–2.05 (m,1H), 2.09–2.17 (m, 1H), 2.71–2.97 (m, 5H), 3.24–3.34 (m, 1H), 4.44–4.52(m, 1H), 6.72 (d, J=8.8 Hz, 2H), 7.55 (d, J=9.2 Hz, 2H) ppm. MS(DCl/NH3): m/z 330 (M+H)⁺.

Example 18BN-{4-[(3R)-1-azabicyclo[2.2.21]oct-3-yloxy]phenyl}-N-phenylamine

The product of Example 18A (270 mg, 0.82 mmol) was treated with aniline(Aldrich, 114 mg, 1.23 mmol) according to the procedure of Example 17A.The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) as an oil (130 mg, yield,54%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.53 (m, 1H), 1.62–1.85 (m, 2H),1.93–2.20 (m, 2H), 2.80–2.94 (m, 5H), 3.18–3.25 (m, 1H), 4.38–4.46 (m,1H), 6.73 (tt, J=7.5, 3.0 Hz, 1H), 6.82 (dt, J=1, 3.4 Hz, 2H), 6.91–6.96(m, 2H), 7.02 (dt, J=9.1, 2.4 Hz, 2H), 7.11–7.18 (m, 2H) ppm. MS(DCl/NH₃) m/z 295 (M+H)⁺.

Example 18CN-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-N-phenylaminehydrochloride

The product of Example 18B (130 mg, 0.44 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The titlecompound was obtained as a solid (70 mg, yield, 48%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.85–2.20 (m, 3H), 2.30–2.42 (m, 1H), 2.45–2.52 (m, 1H),3.30–3.45 (m, 5H), 3.70–80(m, 1H), 4.80 (m, 1H), 6.78 (tt, J=7.5, 3.0Hz, 1H), 6.90 (dt, J=8.8, 3.4 Hz, 2H), 6.94–6.99 (m, 2H), 7.07 (dt,J=8.8, 3.3 Hz, 2H), 7.12–7.20 (m, 2H) ppm. MS (DCl/NH₃) m/z 295 (M+H)⁺.Anal. Calculated for C₁₉H₂₂N₂O.2.0HCl.0.8H₂O: C, 59.78; H, 6.76; N,7.34. Found: C, 59.93; H, 6.44; N, 6.85.

Example 19 N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]pyridin-3-aminedihydrochloride Example 19AN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]pyridin-3-amine

The product of Example 14B (200 mg, 0.55 mmol) was treated with3-aminopyridine (Aldrich, 78 mg, 0.83 mmol) according to the procedureof Example 17A. The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.10) as an oil (110 mg, yield,68%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.39–1.53 (m, 1H), 1.58–1.90 (m, 2H),2.05–2.31 (m, 2H), 2.75–2.98 (m, 5H), 3.25–3.40 (m, 1H), 4.40–4.50 (m,1H), 6.90 (tt, J=9.1, 3.4 Hz, 1H), 7.09 (dt, J=8.8, 3.4 Hz, 2H), 7.19(dd, J=8.5, 4.7 Hz, 1H), 7.34 (ddd, J=8.5, 2.7, 1.3 Hz, 1H), 7.87 (dd,J=4.8, 1.4 Hz, 1H), 8.14 (d, J=2.7 Hz, 1H) ppm. MS (DCl/NH₃) m/z 296(M+H)⁺.

Example 19B N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]pyridin-3-aminedihydrochloride

The product of Example 19A (110 mg, 0.37 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The titlecompound was obtained as a solid (130 mg, yield, 96%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.85–2.18 (m, 3H), 2.25–2.40 (m, 1H), 2.50–2.58 (m, 1H),3.30–3.50 (m, 5H), 3.78–3.8(m, 1H), 4.92 (m, 1H), 7.08 (dt, J=8.9, 3.7Hz, 2H), 7.26 (dt, J=9.2, 3.7 Hz, 2H), 7.78 (dd, J=8.9, 5.5 Hz, 1H),7.93 (ddd, J=8.8, 2.7, 1.4 Hz, 1H), 8.06 (dt, J=5.4, 1.0 Hz, 1H), 8.17(d, J=3.1 Hz, 1H) ppm. MS (DCl/NH₃) m/z 296 (M+H)⁺. Anal. Calculated forC₁₈H₂₁N₃O.2.0HCl.1.1H₂O: C, 55.70; H, 6.54; N, 10.83. Found: C, 55.55;H, 6.28; N, 11.09.

Example 20 N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]benzamidehydrochloride Example 20AN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]benzamide

The product of Example 14B (260 mg, 0.70 mmol) in 1,4-dioxane (Aldrich,anhydrous, 10 mL) was treated with benzamide (Aldrich, 78 mg, 0.83mmol), Pd₂(dba)₃ (Strem Chemical, 12.8 mg, 0.014 mmol), Xantphos (StremChemicals, 24.3 mg, 0.042 mmol), Cs₂CO₃ (Aldrich, 456 mg, 1.4 mmol) andheated at 80° C. for 20 hours. The mixture was allowed to cool to roomtemperature, diluted with ethyl acetate (20 mL), and washed with brine(2×5 mL). The organic phase was concentrated under reduced pressure andthe title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.30) as oil (170 mg, yield, 76%).¹H NMR (MeOH-d₄, 300 MHz) δ 1.45–1.55 (m, 1H), 1.60–1.90 (m, 2H),2.05–2.30 (m, 2H), 2.75–2.98 (m, 5H), 3.35–3.45 (m, 1H), 4.52–4.58 (m, 1H), 6.72–6.98 (m, 2H), 7.45–7.62(m, 5H), 7.86–7.96 (m, 2H) ppm. MS(DCl/NH₃) m/z 323 (M+H)⁺.

Example 20B N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]benzamidehydrochloride

The product of Example 20A (170 mg, 0.53 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The titlecompound was obtained as solid (110 mg, yield, 58%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.85–1.95 (m, 1H), 1.97–2.08 (m, 1H), 2.10–2.18 (m, 1H),2.25–2.40 (m, 1H), 2.52–2.58 (m, 1H), 3.30–3.50 (m, 5H), 3.78–3.85(m,1H), 4.92 (m, 1H), 7.00 (d, J=9.1 Hz, 2H), 7.50 (t, J=7.8 Hz, 2H), 7.57(t, J=7.1 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.92 (d, J=7.5 Hz, 2H) ppm.MS (DCl/NH₃) m/z 323 (M+H)⁺. Anal. Calculated for C₂₀H₂₂N₂O₂.1.0HCl: C,66.94; H, 6.46; N, 7.81. Found: C, 66.73; H, 6.59; N, 7.64.

Example 21N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-cyclohexylamine fumarateExample 21A 3-(4-bromophenoxy)quinuclidine

3-Hydroxy quinuclidine (Aldrich, 1.27 g, 10 mmol) was treated with4-bromo-iodobenzene (Aldrich, 2.82 g, 10 mmol) according to theprocedure of Example 14A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) as oil(0.85 g, yield, 30%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.40–1.56 (m, 1H),1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m,5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.83 (d, J=9.5 Hz, 2H) 7.37 (d,J=9.2, Hz, 2H), ppm. MS (DCl/NH₃) m/z 282 (M+H)⁺, 284 (M+H)⁺.

Example 21 BN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-cyclohexylamine

The product of Example 21A (281 mg, 1.0 mmol) was treated withcyclohexylamine (Aldrich, 150 mg, 1.5 mmol) according to the procedureof Example 17A. The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.10) as oil (130 mg, yield, 43%).¹H NMR (MeOH-d₄, 300 MHz) δ 1.06–1.45 (m, 6H), 1.60–1.90 (m, 5H),1.93–2.05 (m, 3H), 2.18–2.37 (m, 2H), 3.05–3.28 (m, 5H), 4.30–4.40 (m,1H), 6.65 (d, J=8.8 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH₃)m/z 301 (M+H)⁺.

Example 21CN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-cyclohexylamine fumarate

The product of Example 21B (130 mg, 0.43 mmol) in EtOAc/MeOH (v.10/1 1,5 mL) was treated with fumaric acid (50 mg, 0.43 mmol) at roomtemperature overnight. The title compound was obtained as a solid (121mg, yield, 75%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.06–1.45 (m, 6H),1.61–1.90 (m, 5H), 1.93–2.05 (m, 3H), 2.18–2.37 (m, 2H), 3.05–3.28 (m,5H), 3.46–3.60 (m, 1H), 4.52–4.58 (m, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.69(s, 1H), 6.78 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH₃) m/z 301 (M+H)⁺. Anal.Calculated for C₁₉H₂₈N₂O.0.6C₄H₄O₄: C, 69.45; H 8.28; N, 7.57. Found: C,69.53; H, 8.48; N, 7.47.

Example 22 N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-dithien-3-ylamine fumarate Example 22A 3-(4-nitrophenoxy)quinuclidine

3-Hydroxy quinuclidine (Aldrich, 2.54 g, 10 mmol) was treated with1-iodo-4-nitro-benzene (5 g, 20 mmol) according to the procedure ofExample 14A. The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) (1.02 g, yield, 21%). ¹H NMR(MeOH-d₄, 300 MHz) δ 1.40–1.56 (m, 1H), 1.65–1.90 (m, 2H), 1.90–2.08 (m,1H), 2.15–2.25 (m, 1H), 2.75–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.69 (m,1H), 7.07 (d, J=9.5 Hz, 2H), 8.21 (d, J=9.2, Hz, 2H) ppm. MS (DCl/NH₃)m/z 249 (M+H)⁺.

Example 22B 4-(1-azabicyclo[2.2.2]oct-3-yloxy)aniline

The product of Example 22A (1.02 g, 4.1 mmol) in MeOH (25 mL) wastreated with Pd/C (Aldrich, 10%, 150 mg) under H₂ at room temperaturefor 1.5 hours. The mixture was filtered through a short column ofdiatomaceous earth and the filtrate was concentrated under reducedpressure to provide the title compound (0.92 g, yield, 100%). ¹H NMR(MeOH-d₄, 300 MHz) δ 1.40–1.56 (m, 1H), 1.65–1.90 (m, 2H), 1.96–2.13 (m,2H), 2.70–3.00 (m, 5H), 3.10–3.20 (m, 1H), 4.35 (m, 1H), 6.65–6.78 (m,4H) ppm. MS (DCl/NH₃) m/z 219 (M+1)⁺.

Example 22CN-[4-(1-azabicyclo[2.2.21]oct-3-yloxy)phenyl]-N,N-dithien-3-ylamine

The product of Example 22B (219 mg, 1.0 mmol) in toluene (5 mL) wastreated with 3-bromothiophene (Aldrich, 178 mg, 1.1 mmol), Pd₂(dba)₃(Strem Chemicals, 24 mg, 0.025 mmol), (^(t)Bu₃P)₂ Pd (Strem Chemicals,26 mg, 0.05 mmol), sodium tert-butoxide (Aldrich, 105 mg, 1.1 mmol) andheated at 110° C. under N₂ for 15 hours. The mixture was diluted withethyl acetate (20 mL) and washed with water (2×5 mL). The organic phasewas concentrated and the title compound was purified by preparative HPLC(Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Solvent,acetonitrile/H₂O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.)Flow rate, 75 mL/min. uv, 250 nM) as an oil (102 mg, yield, 27%). ¹H NMR(MeOH-d₄, 300 MHz) δ 1.40–1.50 (m, 1H), 1.60–1.85 (m, 2H), 2.00–2.19 (m,2H), 2.71–3.00 (m, 5H), 3.25–3.34 (m, 1H), 4.40–4.50 (m, 1H), 6.54 (dd,J=3.4, 1.4 Hz, 2H), 6.80 (dd, J=1.7, 5.1 Hz, 2H), 6.86 (d, J=9.2 Hz,2H), 7.03 (d, J=9.2 Hz, 2H), 7.29 (dd, J=3.1, 5.4 Hz 2H) ppm. MS(DCl/NH₃) m/z 383 (M+H)⁺.

Example 22DN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-dithien-3-ylaminefumarate

The product of Example 22C (102 mg, 0.27 mmol) in ethyl acetate:MeOH (5mL, 10:1) was treated with fumaric acid (35 mg, 0.30 mmol) at roomtemperature overnight. The title compound was obtained as a solid (125mg, yield, 89%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.75–2.02 (m, 2H),2.08–2.37 (m, 2H), 2.45–2.55 (m, 1H), 3.19–3.42 (m, 5H), 3.70–3.80 (m,1H), 4.80 (m, 1H), 6.58 (dd, J=3.1, 1.4 Hz, 2H), 6.69 (s, 2.5H), 6.80(dd, J=5.4, 1.4 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.06 (d, J=9.2 Hz, 2H),7.82 (dd, J=5.1, 3.1 Hz, 2H) ppm. MS (DCl/NH₃) m/z 383 (M+H)⁺. Anal.Calculated. for C₂₁H₂₂N₂OS₂.1.25C₄H₄O₄ C, 59.19; H 5.16; N, 5.31. Found:59.14; H, 4.91; N, 5.25.

Example 23N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-1,3-thiazol-2-yl-1,3-thiazol-2-aminedihydrochloride Example 23AN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-1,3-thiazol-2-yl-1,3-thiazol-2-amine

The product of Example 22B (219 mg, 1.0 mmol) was treated with2-bromothiazole (Aldrich, 179 mg, 1.1 mmol) according to the procedureof Example 22C. The title compound was purified by preparative HPLC asan oil (42 mg, yield, 11%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.45–1.54 (m,1H), 1.65–1.88 (m, 2H), 2.00–225 (m, 2H), 2.75–3.03 (m, 5H), 3.35–3.42(m, 1H), 4.60–4.66 (m, 1H), 7.02–7.06 (m, 2H), 7.10–7.17 (m, 2H),7.33–7.39 (m, 4H) ppm. MS (DCl/NH₃) m/z 385 (M+H)⁺.

Example 23BN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-1,3-thiazol-2-yl-1,3-thiazol-2-aminedihydrochloride

The product of Example 23A (42 mg, 0.11 mmol) in ethyl acetate (3 mL)was treated with 4M HCl in 1,4-dioxane (0.2 mL, 0.8 mmol) at ambienttemperature for 10 hours. The title compound was obtained as a solid (22mg, yield, 40%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.87–2.23(m, 3H), 2.30–2.40(m, 1H), 2.55–2.64 (m, 1H 3.30–3.50 (m, 5H), 3.85–3.92 (m, 1H), 5.05 (m,1H), 7.23 (d, J=4.1 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.52 (d, J=3.7Hz,2H), 7.60 (d, J=8.8 Hz, 2H) ppm. MS (DCl/NH₃) m/z 385 (M+H)⁺. Anal.Calculated for C₁₉H₂₀N₄OS₂.2HCl.2H₂O: C, 46.25; H 5.31; N, 11.35. Found:C, 46.41; H, 5.06; N, 11.09.

Example 24N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-bis(1-benzothien-3-yl)aminehydrochloride Example 24AN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-bis(1-benzothien-3-yl)amine

The product of Example 22B (219 mg, 1.0 mmol) was treated with3-bromo-1-benzothiophene (Aldrich, 233 mg, 1.1 mmol) according to theprocedure of Example 21C. The title compound was purified by preparativeHPLC as an oil (70 mg, yield, 14%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.40–1.75 (m, 3H), 1.90–2.05 (m, 2H), 2.64–296 (m, 5H), 3.10–3.20 (m,1H), 4.20–4.28 (m, 1H), 6.57 (s, 4H), 7.23–7.42 (m, 4H), 7.58–7.68 (m,2H), 7.81–7.98 (m, 4H) ppm. MS (DCl/NH₃) m/z 483 (M+1)⁺.

Example 24BN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-bis(1-benzothien-3-yl)aminehydrochloride

The product of Example 24A (70 mg, 0.14 mmol) in ethyl acetate (3 mL)was treated with 4M HCl in 1,4-dioxane (0.2 mL, 0.8 mmol) at ambienttemperature for 10 hours. The title compound was obtained as a solid (42mg, yield, 53%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.85–2.25(m, 3H), 2.30–2.40(m, 1H), 3.17–3.44 (m, 6H), 3.60–3.68 (m, 1H), 4.61 (m, 1H), 6.56–6.68(m, 4H), 7.26–7.44 (m, 5H), 7.61–7.67 (m, 2H), 7.84–7.97 (m, 3H) ppm. MS(DCl/NH₃) m/z 483 (M+H)⁺. Anal. Calculated for C₂₉H₂₆N₂OS₂.HCl.1.5H₂O:C, 63.78; H 5.54; N, 5.13. Found: C, 63.76; H, 5.65 ; 4.84.

Example 251-(5-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]amino}thien-2-yl)ethanonehydrochloride Example 25A1-(5-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]amino}thien-2-yl)ethanone

The product of Example 22B (219 mg, 1.0 mmol) was treated with1-(5-bromothien-2-yl)ethanone (Aldrich, 227 mg, 1.1 mmol) according tothe procedure of Example 22C. The title compound was purified bypreparative HPLC as an oil (40 mg, yield, 12%). ¹H NMR (MeOH-d₄, 300MHz) δ 1.45–1.84 (m, 3H), 2.00–2.18 (m, 2H), 2.40 (s, 3H), 2.75–2.98 (m,5H), 3.25–3.32 (m, 1H), 4.49 (m, 1H), 6.36 (d, J=4.4 Hz, 1H), 6.92 (d,J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.63 (d, J=4.4 Hz, 1H) ppm. MS(DCl/NH₃) m/z 343 (M+H)⁺.

Example 25B1-(5-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]amino}thien-2-yl)ethanonehydrochloride

The product of Example 25A (40 mg, 0.12 mmol) was treated with HCl(Aldrich, in dioxane, 4M, 0.2 mL, 0.8 mmol) in ethyl acetate (3 mL) atambient temperature for 10 h. The title compound was obtained as solid(37 mg, yield, 64%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.82–2.19(m, 3H),2.30–2.38 (m, 1H), 2.41 (s, 3H), 2.46–2.55 (m, 1H), 3.23–3.47 (m, 5H),3.76–3.84 (m, 1H), 4.78–4.85 (m, 1H), 6.40 (d, J=4.4 Hz, 1H), 7.00 (d,J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.65 (d, J=4.4 Hz, 1H) ppm. MS(DCl/NH₃) m/z 343 (M+H)⁺.

Example 26N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-(4-methylthien-3-yl)aminehydrochloride Example 26AN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-(4-methylthien-3-yl)amine

The product of Example 22B (219 mg, 1.0 mmol) was treated with3-bromo-4-methylthiophene (Aldrich, 196 mg, 1.1 mmol) according to theprocedure of Example 22C. The title compound was purified by preparativeHPLC as an oil (180 mg, yield, 57%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.45–1.84 (m, 3H), 1.97–2.15 (m, 2H), 2.70–300 (m, 5H), 3.25–3.32 (m,1H), 4.39 (m, 1H), 6.60 (d, J=3.4 Hz, 1H), 6.75–6.83 (m, 2H), 6.87–6.96(m, 3H) ppm. MS (DCl/NH₃) m/z 315 (M+H)⁺.

Example 26BN-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-(4-methylthien-3-yl)aminehydrochloride

The product of Example 26A (198 mg, 0.57 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol) at ambienttemperature for 10 hours. The title compound was obtained as a solid(155 mg, yield, 77%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.80–2.02(m, 2H),2.03–2.16 (m, 4H), 2.30–2.38 (m, 1H), 2.46–2.55 (m, 1H), 3.20–3.47 (m,5H), 3.72–3.80 (m, 1H), 4.68–4.75 (m, 1H), 6.66 (d, J=3.4 Hz, 1H),6.83–6.99 (m, 5H) ppm. MS (DCl/NH₃) m/z 315 (M+H)⁺. Anal. Calculated forC₁₈H₂₂N₂OS.1.05HCl C, 61.29; H 6.59; N, 7.94. Found: C, 61.25; H, 6.50;N, 7.82.

Example 27 3-[(6-phenoxypyridazin-3-yl)oxy]quinuclidine hydrochlorideExample 27A 3-chloro-6-phenoxypyridazine

3,6-Dichloropyridazine (Aldrich, 4.47 g, 30 mmol) in NaOH (10%, 20 mL)was treated with phenol (Aldrich, 1.88 g, 20 mmol) at 100° C. for 15hours. After cooling to room temperature, the mixture was extracted withethyl acetate (2×50 mL). The extracts were combined and concentratedunder reduced pressure. The title compound was purified bychromatography (SiO₂, Hexanes: ethyl acetate=80: 20, R_(f). 0.5) as asolid (3.8 g, yield, 92%). ¹H NMR (CDCl₃, 300 MHz) δ 7.11–7.29 (m, 3H),7.38–7.55 (m, 4H) ppm. MS (DCl/NH₃) m/z 207 (M+H)⁺, 209 (M+H)⁺.

Example 27B 3,6-diphenoxypvridazine

Phenol (Aldrich, 1.88 g, 20 mmol) in tetrahydrofuran (50 mL) was treatedwith potassium tert-butoxide (Aldrich, 2.24 g, 20 mmol) at ambienttemperature for 10 minutes. The product of Example 27A (3.0 g, 14.5mmol) was then added and the reaction mixture was stirred at 60° C. for10 hours. The mixture was allowed to cool to room temperature, dilutedwith ethyl acetate (100 mL), and washed with brine (2×10 mL). Theorganic phase was concentrated affording the title compound as a solid(3.2 g, yield, 84%). ¹H NMR (MeOH-d₄, 300 MHz) δ 7.14–7.28 (m, 6H),7.38–7.48 (m, 6H) ppm. MS (DCl/NH₃) m/z 265(M+H)⁺.

Example 27C 3-[(6-phenoxypyridazin-3-yl)oxy]quinuclidine

3-Hydroxy quinuclidine (Aldrich, 160 mg, 1.25 mmol) in tetrahydrofuranwas treated with potassium tert-butoxide (112 mg, 1.0 mmol) at ambienttemperature for 10 minutes. The product of Example 27B (528 mg, 2 mmol)was added. The mixture was stirred at ambient temperature for 6 hours.The mixture was diluted with ethyl acetate (20 mL) and washed with brine(2×5 mL). The organic phase was concentrated and the title compound waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f).0.20) as oil (120 mg, yield, 45%). ¹H NMR (MeO H-d₄300 MHz) δ 1.48–1.58(m, 1H), 1.60–1.90 (m, 2H), 1.96–2.10 (m, 1H), 2.24–2.30 (m, 1H),2.77–2.98 (m, 5H), 3.40–3.50 (m, 1H), 5.10–5.20 (m, 1H), 7.11–7.16 (m,2H), 7.20–7.26(m, 1H), 7.25(d, J=9.5 Hz, 1H), 7.30 (d, J=9.5 Hz, 1H),7.38–7.45 (m, 2H) ppm. MS (DCl/NH₃) m/z 265 (M+H)⁺.

Example 27D 3-[(6-phenoxypyridazin-3-yl)oxy]quinuclidine hydrochloride

The product of Example 27C (120 mg, 0.45 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The titlecompound was obtained as a solid (120 mg, yield, 80%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.85–2.18 (m, 1H), 2.30–2.45 (m, 1H), 2.56–2.64 (m, 1H),3.35–3.50 (m, 5H), 3.85–3.9(m, 1H), 5.45 (m, 1H), 7.18–7.26 (m, 2H),7.28–7.36 (m, 1H), 7.45–7.51 (m, 2H), 7.52 (s, 2H) ppm. MS (DCl/NH₃) m/z265 (M+H)⁺. Anal. Calculated for C₂₀H₂₂N₂O₂.2.0HCl: C, 55.14; H, 5.72;N, 11.35. Found: C, 55.03; H, 5.59; N, 11.64.

Example 28 3-[(5-phenoxypyridin-2-yl)oxy]quinuclidine hydrochlorideExample 28A 3-[(5-phenoxypyridin-2-yl)oxy]quinuclidine

3-Hydroxy quinuclidine (Aldrich, 3.2 g, 25 mmol)) in DMF (anhydrous, 30mL) was treated with NaH (Aldrich, 99%, 1.2 g, 50 mmol) at ambienttemperature for 1 hour. 2-Chloro-5-bromopyridine (7.1 g, 30 mmol) wasadded and the mixture was stirred at 100° C. for 6 hours. The mixturewas allowed to cool to room temperature, treated with Na₂CO₃ (2M, 10 mL)at 10° C., and extracted with ethyl acetate (2×50 mL). The extracts werecombined and concentrated under reduced pressure. The title compound waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃H₂O, 90:10:2, R_(f).0.20) as oil (5.3 g, yield, 75%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.46–1.58(m, 1H), 1.60–1.88 (m, 2H), 1.96–2.10 (m, 1H), 2.24–2.30 (m, 1H),2.72–2.98 (m, 5H), 3.42–3.46 (m, 1H), 5.00–5.08 (m, 1H), 6.75 (d, J=8.8Hz, 1H), 7.77 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (d, J=2.7, 1H) ppm. MS(DCl/NH₃) m/z 283 (M+H)⁺, 285 (M+H)⁺

Example 28B 3-[(5-phenoxypyridin-2-yl)oxy]quinuclidine

The product of Example 28A (283 mg, 1 mmol) was treated with phenol(Aldrich, 188 mg, 2 mmol) according the procedure of Example 14C. Thetitle compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.10) as an oil (210 mg, yield,71%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.46–1.58 (m, 1H), 1.60–1.88 (m, 2H),1.96–2.10 (m, 1H), 2.24–2.30 (m, 1H), 2.75–3.02 (m, 5H), 3.46–3.50 (m,1H), 5.10–5.15 (m, 1H), 6.75–6.84 (m, 2H), 6.90–7.00 (m, 2H), 7.25–7.42(m, 2H), 7.78 (dd, J=8.8, 2.3 Hz, 1H), 7.86 (d, J=3.0 Hz, 1H) ppm. MS(DCl/NH₃) m/z 297 (M+H)⁺.

Example 28C 3-[(5-phenoxypyridin-2-yl)oxy]quinuclidine hydrochloride

The product of Example 28B (210 mg, 0.71 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The titlecompound was obtained as a solid (120 mg, yield, 80%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.85–2.20 (m, 3H), 2.30–2.45 (m, 1H), 2.56–2.64 (m, 1H),3.35–3.50 (m, 5H), 3.80–3.9(m, 1H), 5.35 (m, 1H), 6.88–7.00 (m, 3H),7.06–7.14 (m, 1H), 7.30–7.38 (m, 2H), 7.45 (dd, J=8.8, 3.0 Hz, 1H), 7.88(d, J=2.3 Hz, 1H) ppm. MS (DCl/NH₃) m/z 297 (M+H)⁺. Anal. Calculated forC₂₀H₂₀N₂O₂.1.0HCl.0.3H₂O: C, 63.92; H, 6.44; N, 8.28. Found: 63.97; H,6.49; N, 8.17.

Example 29 3-[(5-phenoxypyrimidin-2-yl)oxy]quinuclidine fumarate Example29A 3-[(5-bromopyrimidin-2-yl)oxy]quinuclidine

3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran (10ml) was treated with potassium tert-butoxide (Aldrich, 224 mg, 2 mmol)at ambient temperature for 1 hour. The mixture was treated with2-iodo-5-bromo-pyrimidine (TCl, 568 mg, 2 mmol), stirred at roomtemperature for 1 hour, treated with water (5 mL), and extracted withchloroform:isopropyl alcohol (10:1) (3×20 mL). The extracts werecombined and concentrated. The title compound was purified bychromatography (SiO₂, CH₂Cl₂: MeOH: NH₃H₂O, 90:10:2, R_(f). 0.20) as oil(210 mg, yield, 71%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.56–1.68 (m, 1H),1.70–1.90 (m, 2H), 2.05–2.30 (m, 2H), 2.79–3.06 (m, 5H), 3.40–3.48 (m,1H), 5.11 (m, 1H), 8.64 (s, 2h) ppm. MS (DCl/NH₃) m/z 284 (M+H)⁺, 286(M+H)⁺.

Example 29B 3-[(5-phenoxypyrimidin-2-yl)oxy]quinuclidine fumarate

The product of Example 29A (284 mg, 1.0 mmol) was treated with phenol(Aldrich, 188 mg, 2 mmol) according to the procedure of Example 14C. Thefree base of the title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃H₂O, 90:10:2, R_(f). 0.15) as an oil (42 mg, yield, 14%).The free base of the title compound (42 mg, 0.14 mmol) in ethylacetate:MeOH (3 mL, 10:1) was treated with fumaric acid (18 mg, 0.15mmol) at room temperature for 10 hours. The title compound was obtainedas a solid (22 mg, 36%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.84–2.18 (m, 3H),2.25–2.38 (m, 1H), 2.50–2.58 (m, 1H), 3.23–3.44 (m, 5H), 3.80–3.88 (m,1H), 5.32 (m, 1H), 6.69 (s, 2.5H), 7.00–7.06(m, 2H), 7.15–7.20 (m, 2H),8.39 (s, 2H) ppm. MS (DCl/NH₃) m/z 298 (M+H)⁺. Anal. Calculated forC₁₇H₁₉N₃O₂.1.26C₄H₄O₄: C, 59.67; H 5.46; N, 9.47. Found: C, 59.43; N,9.51.

Example 30 N-(4-phenoxyphenyl)quinuclidin-3-amine dihydrochlorideExample 30A N-(4-phenoxyphenyl)quinuclidin-3-amine

3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) in acetic acid(25 mL) was treated with 4-phenoxyaniline (Aldrich, 0.93 g, 5.0 mmol),Na₂SO₄ (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)₃ (Aldrich,3.16 g, 15 mmol) at ambient temperature for 15 hours. The reactionmixture was slowly poured into a flask containing 75 mL of saturatedNaHCO₃, stirred for 20 minutes, and extracted with ethyl acetate (3×100mL). The extracts were combined and washed with brine (2×20 mL). Theorganic phase was concentrated under reduced pressure and the titlecompound was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O,90:10:2, R_(f). 0.10) as a solid (1.46 g, yield, 99%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.78–1.90 (m, 1H), 2.00–2.10 (m, 2H), 2.22–2.35 (m, 2H), 3.05(ddd, J=12.9, 4.7, 2.0 Hz, 1H) 3.20–3.40 (m, 4H), 3.78 (ddd, J=12.9,9.5, 2.4 Hz, 1H), 3.90–3.98 (m, 1H), 6.65–6.75 (m, 2H), 6.80–6.90 (m,4H), 6.99 (tt, J=7.5, 1.0 Hz, 1H), 7.20–7.29 (m, 2H) ppm. MS (DCl/NH₃)m/z 295 (M+H)⁺.

Example 30B N-(4-phenoxyphenyl)quinuclidin-3-amine dihydrochloride

The product of Example 30A (1.46 g, 4.9 mmol) in ethyl acetate (20 mL)was treated with 4M HCl in 1,4-dioxane (5 mL, 20 mmol). The titlecompound was obtained as a solid (1.40 g, yield, 77%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.90–2.00 (m, 1H), 2.05–2.15 (m, 2H), 2.35–2.45 (m, 2H), 3.15(ddd, J=12.9, 5.1, 2.4 Hz, 1H) 3.30–3.50 (m, 4H), 3.80 (ddd, J=12.9,9.5, 2.7 Hz, 1H), 3.95–4.10 (m, 1H), 6.85–7.00 (m, 6H), 7.04 (tt, J=8.4,1.0 Hz, 1H), 7.26–7.32 (m, 2H) ppm. MS (DCl/NH₃) m/z 295 (M+H)⁺. Anal.Calculated for C₁₉H₂₂N₂O.2.0HCl: C, 62.13; H, 6.59; N, 7.63. Found: C,62.01; H, 6.53; N, 7.49.

Example 31 N-[4-(4-chlorophenoxy)phenyl]quinuclidin-3-aminehydrochloride

3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treatedwith 4-(4-chlorophenyloxy) aniline (Aldrich, 1.10 g, 5.0 mmol) accordingto the procedure of Example 30A. The free base of the title compound waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f).0.10) as a solid (1.52 g, yield, 93%). MS (DCl/NH₃) m/z 329 (M+H)⁺, 331(M+H)⁺. The free base (200 mg, 0.61 mmol) was treated with 4M HCl1,4-dioxane (0.5 mL, 2.0 mmol) in ethyl acetate (5 mL). Thehydrochloride salt of the title compound was obtained as a solid (195mg, yield, 80%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.90–2.18 (m, 3H),2.35–2.45 (m, 2H), 3.24 (ddd, J=12.5, 5.4, 2.3 Hz, 1H) 3.30–3.50 (m,4H), 3.82 (ddd, J=12.2, 9.8, 2.7 Hz, 1H), 3.95–4.10 (m, 1H), 6.91 (dt,J=9.1, 2.3 Hz, 2H), 6.95–7.02 (m, 4H), 7.30(dt, J=9.2, 2.4 Hz, 1H),7.26–7.32 (m, 2H) ppm. MS (DCl/NH₃) m/z 329 (M+H)⁺, 331 (M+H)⁺. AnalCalculated for C₁₉H₂₁ClN₂O.2.0HCl.0.5H₂O: C, 55.56; H, 5.89; N, 6.82.Found: C, 55.78; H, 5.28; N, 6.62.

Example 32 N-[4-(4-methylphenoxy)phenyl]quinuclidin-3-aminehydrochloride Example 32A N-[4-(4-methylphenoxy)phenyl]quinuclidin-3-amine

3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treatedwith 4-(4-methylphenoxy)aniline (0.99 g, 5.0 mmol) according to theprocedure of Example 30A. The title product was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.10) as anoil (1.48 g, yield, 95%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.55–1.70 (m, 1H),1.78–1.95 (m, 2H), 2.00–2.15 (m, 2H), 2.28 (s, 3H), 2.71 (ddd, J=12.9,5.1, 2.2 Hz, 1H), 2.95–3.10 (m, 4H), 3.46 (ddd, J=12.9, 9.5, 2.4 Hz,1H), 3.60–3.70 (m, 1H), 6.64 (dt, J=9.0, 2.7 Hz, 2H), 6.72–6.84 (m, 4H),7.06 (dt, J=9.1, 2.8 Hz, 2H) ppm. MS (DCl/NH₃) m/z 309 (M+H)⁺.

Example 32B N-[4-(4-methylphenoxy)phenyl]quinuclidin-3-aminehydrochloride

The product of Example 32A (200 mg, 0.65 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in dioxane (0.5 mL). The title compound wasobtained as a solid (180 mg, yield, 73%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.96–2.17 (m, 3H), 2.31 (s, 3H), 2.34–2.41 (m, 2H), 3.26–3.54 (m, 5H),3.81 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 4.06–4.13 (m, 1H), 6.85 (dt, J=9.0,2.7 Hz, 2H), 6.97 (dt, J=9.1, 2.7 Hz, 2H) 7.09–7.17 (m, 4H), ppm. MS(DCl/NH₃) m/z 309 (M+H)⁺. Anal. calculated for C₂₀H₂₄N₂O.2.0HCl.1.0H₂O:C, 60.15; H, 7.07; N, 7.01. Found: C, 60.34; H, 7.14; N, 6.98.

Example 33 N-[4-(4-aminophenoxy)phenyl]quinuclidin-3-amine Example 33AN-[4-(4-aminophenoxy)phenyl]guinuclidin-3-amine

3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treatedwith 4-(4-aminophenoxy)phenylamine (1.00 g, 5.0 mmol) according to theprocedure of Example 30A. The title product was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 80:20:4, R_(f). 0.20) as anoil (0.98 g, yield, 63%). ¹H NMR (MeOH-d₄, 300 MHz) 61.55–1.70 (m, 1H),1.80–1.95 (m, 2H), 1.98–2.15 (m, 2H), 2.68 (ddd, J=12.9, 5.1, 2.7 Hz,1H), 2.88–3.11 (m, 4H), 3.42 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 3.59–3.65(m, 1H), 6.58–6.84 (m, 8H) ppm. MS (DCl/NH₃) m/z 310 (M+H)⁺.

Example 33B N-[4-(4-aminophenoxy)phenyl]quinuclidin-3-aminehydrochloride

The product of Example 33A (150 mg, 0.48 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL). The title compound wasobtained as a solid (150 mg, yield, 82%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.96–2.17 (m, 3H), 2.30–2.30–2.41 (m, 2H), 3.16 (ddd, J=12.9, 5.1, 2.5Hz, 1H), 3.27–3.47 (m, 4H), 3.81 (ddd, J=12.9, 9.5, 2.4 Hz, 1H),4.00–4.10 (m, 1H), 6.89 (dt, J=9.0, 2.7 Hz, 2H), 6.96 (dt, J=9.1, 2.7Hz, 2H) 7.04 (dt, J=9.0, 2.8 Hz, 2H), 7.34 (dt, J=9.0, 3.0 Hz, 2H) ppm.MS (DCl/NH₃) m/z 310 (M+H)⁺. Anal. calculated for C₁₉H₂₃N₃O.3.0HCl.0.9H₂O: C, 52.46; H, 6.44; N, 9.66. Found: C, 52.77; H, 6.91; N, 9.76.

Example 34 4,4′-di(1-aza-bicyclo[2.2.2]oct-3-yl-amino)-diphenylthioether tetra (hydrochloride) Example 34A4,4′-di(1-aza-bicyclo[2.2.2]oct-3-yl-amino)-diphenyl thioether

3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treatedwith 4-(4-aminophenoxy)phenylamine (1.00 g, 5.0 mmol) according to theprocedure of Example 33A. The title product was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 80:20:4, R_(f). 0.10) as anoil (0.26 g, yield, 12%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.34–1.55 (m, 2H),1.59–1.84 (m, 4H), 1.84–2.09 (m, 4H), 2.44–2.64 (m, 2H), 2.68–3.11 (m,8H), 3.19–3.39 (m, 2H), 3.42–3.64 (m, 2H), 6.55–6.66 (m, 4H), 6.67–6.86(m, 4H) ppm. MS (DCl/NH₃) m/z 419 (M+H)⁺.

Example 34B 4,4′-di(1-aza-bicyclo[2.2.2]oct-3-yl-amino)-diphenylthioether tetra(hydrochloride)

The product of Example 34A (270 mg, 0.63 mmol) was treated with HCl(Aldrich, 4 M in dioxane, 1 mL, 4 mmol) in EtOAc (10 mL) at ambienttemperature for 10 hours to give the title compound as solid (260 mg,yield, 75%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.82–2.18 (m, 6H) 2.21–2.48 (m,4H) 3.17–3.59 (m, 10H) 3.75–3.86 (m, 2H) 4.01–4.19 (m, 2H) 6.87–6.99 (m,4H) 6.99–7.10 (m, 4H) ppm. MS (DCl/NH₃) m/z 419 (M+H)⁺. Anal. calculatedfor C₂₆H₃₄N₄O.4.0HCl.4.0 H₂O: C, 49.06; H, 7.28; N, 13.38. Found: C,48.80; H, 6.95; N, 8.59.

Example 35 N-1-azabicyclo[2.2.2]oct-3-yl-N′-phenylbenzene-1,4-diaminehydrochloride Example 35A N-(4-iodophenyl)quinuclidin-3-amine

3-Quinuclidinone hydrochloride (Aldrich, 3.22 g, 20 mmol) was treatedwith 4-iodo-aniline (2.19 g, 10 mmol) according to the procedure ofExample 30A. The title product was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.10) as oil (3.24 g, yield, 98%).¹H NMR (MeOH-d₄, 300 MHz) δ 1.70–1.81 (m, 1H), 1.93–2.04 (m, 2H),2.08–2.24 (m, 2H), 2.89 (ddd, J=12.9, 5.1, 2.7 Hz, 1H), 3.12–3.28 (m,4H), 3.64 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 3.79–3.85 (m, 1H), 6.46 (dt,J=9.0, 2.7 Hz, 2H), 7.39 (dt, J=9.1, 2.7 Hz, 2H) ppm. MS (DCl/NH₃) m/z329 (M+H)⁺.

Example 35B N-(4-iodophenyl)quinuclidin-3-amine hydrochloride

The product of Example 35A (100 mg, 0.30 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL). The title compound wasobtained as solid (90 mg, yield, 75%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.80–1.92 (m, 1H), 2.00–2.10 (m, 2H), 2.18–2.32 (m, 2H), 3.03 (ddd,J=12.9, 5.1, 2.7 Hz, 1H), 3.28–3.41 (m, 4H), 3.78 (ddd, J=12.9, 9.5, 2.4Hz, 1H), 3.90–3.96 (m, 1H), 6.49 (dt, J=9.0, 2.7 Hz, 2H), 7.42 (dt,J=9.1, 2.7 Hz, 2H) ppm. MS (DCl/NH₃) m/z 329 (M+H)⁺. Anal. calculatedfor C₁₃H₁₇IN₂.2.0HCl: C, 38.93; H, 4.77; N, 6.98. Found: C, 39.07; H,4.53; N, 6.80.

Example 35C N-1-azabicyclo[2.2.2]oct-3-yl-N′-phenylbenzene-1,4-diamine

The product of Example 35A (200 mg, 0.61 mmol) was treated with aniline(Aldrich, 93 mg, 1 mmol) according to the procedure of Example 17A. Thetitle product was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O,90:10:2, R_(f). 0.20) as an oil (120 mg, yield, 68%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.45–1.57 (m, 1H), 1.72–1.84 (m, 2H), 1.93–2.06 (m, 2H), 2.63(ddd, J=12.9, 5.1, 2.7 Hz, 1H), 2.82–2.99 (m, 4H), 3.30–3.40 (m, 1H),3.56–3.64 (m, 1H), 6.56–7.13 (m, 9H) ppm. MS (DCl/NH₃) m/z 294 (M+H)⁺.

Example 35D N-1-azabicyclo[2.2.2]oct-3-yl-N′-phenylbenzene-1,4-diaminehydrochloride

The product of Example 35C (120 mg, 0.40 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL). The title compound wasobtained as a solid (100 mg, yield, 69%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.86–2.11 (m, 3H), 2.25–2.41 (m, 2H), 3.16 (ddd, J=12.9, 5.1, 2.5 Hz,1H), 3.27–3.47 (m, 4H), 3.80 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 4.00–4.07(m, 1H), 6.83–6.91 (m, 4H), 7.13–7.33 (m, 5H) ppm. MS (DCl/NH₃) m/z 294(M+H)⁺. Anal. calculated for C₁₉H₂₃N₃.2.4HCl .1.0H₂O: 57.20; H, 6.92; N,10.53. Found: C, 57.25; H, 7.00; N, 10.53.

Example 36 3-[(4-phenoxyphenyl)thio]quinuclidine hydrochloride Example36A 3-[(4-bromophenyl)thio]quinuclidine

4-Bromobenzenethiol (Aldrich, 2.54 g, 24 mmol) in DMF (anhydrous,Aldrich, 40 mL) was treated with NaH (Aldrich, 95%,1.27 g, 48 mmol) atambient temperature. After stirring for 20 minutes, the mixture wastreated with 3-chloroqunuclidine hydrochloride (Aldrich, 3.64 g, 20mmol) and stiired under N₂ at 100° C. for 18 hours. The mixture wascooled down to room temperature, treated with water (300 mL), andextracted with ethyl acetate (3×100 mL). The extracts were combined andwashed with brine (2×30 mL). The organic phase was concentrated givingthe title product as a brown oil (3.40 g, yield, 57%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.48–1.60 (m, 1H), 1.64–1.92 (m, 2H), 2.05–2.19 (m, 2H), 2.65(ddd, J=13.9, 5.7, 1.7 Hz, 1H), 2.81–2.97 (m, 4H), 3.39 (ddd, J=13.9,9.8, 2.4 Hz, 1H), 3.37–3.63 (m, 1H), 7.30 (dt, J=8.5, 2.7 Hz, 2H), 7.45(dt, J=8.4, 2.7 Hz, 2H) ppm. MS (DCl/NH₃) m/z 298 (M+H)⁺, 300 (M+H)⁺.

Example 36B 3-[(4-phenoxyphenyl)thio]quinuclidine

The product of Example 36A (300 mg, 1.0 mmol) was treated with phenol(Aldrich, 188 mg, 2 mmol) according to the procedure of Example 2A. Thetitle product was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O,90:10:2, R_(f). 0.20) as an oil (220 mg, yield, 71%). ¹H NMR (MeOH-d₄,300 MHz) δ 1.45–1.66 (m, 2H), 1.77–1.98 (m, 2H), 2.13–2.24 (m, 1H), 2.62(ddd, J=13.6, 5.4, 2.0 Hz, 1H), 2.76–2.92 (m, 4H), 3.29–3.40 (m, 1H),3.44–3.54 (m, 1H), 6.92 (dt, J=9.0, 2.7 Hz, 2H), 6.97–7.01 (m, 2H),7.00–7.14 (m, 1H), 7.32–7.44 (m, 4H) ppm. MS (DCl/NH₃) m/z 312 (M+H)⁺.

Example 36C 3-[(4-phenoxyphenyl)thio]quinuclidine hydrochloride

The product of Example 36B (220 mg, 0.71 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL). The title compound wasobtained as a solid (180 mg, yield, 73%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.84–2.02 (m, 2H), 2.05–2.20 (m, 2H), 2.37–2.52 (m, 1H), 3.14 (ddd,J=17.6, 10.5 2.4 Hz, 1H), 3.24–3.45 (m, 4H), 3.70–3.79 (m, 2H), 6.92(dt, J=8.9, 3.0 Hz, 2H), 6.97–7.08(m, 2H), 7.13–7.19 (m, 1H), 7.30–7.42(m, 2H), 7.50 (dt, J=9.0, 3.0 Hz, 2H) ppm. MS (DCl/NH₃) m/z 312 (M+H)⁺.Anal. calculated for C₁₉H₂₁NOS.1.0HCl.0.9H₂O: C, 62.67; H, 6.59; N,3.85Found: C, 62.31; H, 6.31; N, 4.23.

Example 37 N-[4-(1-azabicyclo[2.2.2]oct-3-ylthio)phenyl]-N-phenylaminedihydrochloride Example 37AN-[4-(1-azabicyclo[2.2.2]oct-3-ylthio)phenyl]-N-phenylamine

The product of Example 36A (300 mg, 1.0 mmol), as described herein, wastreated with aniline (Aldrich, 186 mg, 2 mmol) according to theprocedure of Example 17A, as described herein. The title product waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f).0.10) as an oil (210 mg, yield, 68%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.42–1.64 (m, 2H), 1.74–1.85 (m, 2H), 2.15–2.27 (m, 1H), 2.62 (ddd,J=13.9, 4.7, 1.7 Hz, 1H), 2.77–2.95 (m, 4H), 3.21–3.40 (m, 2H), 6.87(tt, J=7.4, 1.0 Hz, 1H), 7.01 (dt, J=8.8, 1.7 Hz, 2H), 7.05–7.10 (m,2H), 7.19–7.25 (m, 2H), 7.30 (dt, J=8.8, 2.0 Hz, 2H) ppm. MS (DCl/NH₃)m/z 311 (M+H)⁺.

Example 37B N-[4-(1-azabicyclo[2.2.2]oct-3-ylthio)phenyl]-N-phenylamineDihydrochloride

The product of Example 37A (210 mg, 0.68 mmol) in ethyl acetate (5 mL)was treated with 4M HCl in 1,4-dioxane (0.5 mL). The title compound wasobtained as a solid (150 mg, yield, 58%). ¹H NMR (MeOH-d₄, 300 MHz) δ1.83–1.99 (m, 2H), 2.03–2.17 (m, 2H), 2.43–2.54 (m, 1H), 3.12 (ddd,J=12.5, 5.4 2.4 Hz, 1H), 3.26–3.46 (m, 4H), 3.58–3.75 (m, 2H), 6.91 (tt,J=7.4, 1.0 Hz, 1H), 7.04 (dt, J=8.8, 2.0 Hz, 2H), 7.09–7.12 (m, 2H),7.22–7.25 (m, 2H), 7.38 (dt, J=8.8, 2.0 Hz, 2H) ppm. MS (DCl/NH₃) m/z311 (M+H)⁺. Anal. calculated for C₁₉H₂₂N₂S.2.0HCl.1.5H₂O: C, 55.47; H,6.86; N, 6.81. Found: C, 55.72; H, 6.67; N, 6.26.

Example 38

3-[4-(4-iodo-phenoxy)-phenoxy]-1-aza-bicyclo[2.2.2]octane Hydrochloride

Example 38A 3-[4-(4-iodo-phenoxy)-phenoxy]-1-aza-bicyclo[2.2.2]octane

3-Hydroxy quinuclidine (Aldrich, 1.27 g, 10.0 mmol) was treated with4,4′-diiodo-diphenyl ether (Aldrich, 4.22 g, 10 mmol), Cul (StremChemicals, 190 mg, 1.0 mmol), 1,10-phenanthroline (Aldrich, 360 mg, 2.0mmol) and Cs₂CO₃ (6.60 g, 20.0 mmol) in toluene (anhydrous, Aldrich, 20mL) and heated at 110° C. for two days according to the procedure ofExample 2A. The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃ H₂O, 90:10:1, R_(f). 0.20) as solid (570 mg, yield,13%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.77–2.20 (m, 3H), 2.23–2.39 (m, 1 H),2.42–2.57 (m, 1H), 3.31–3.49 (m, 6 H,) 3.80 (m, 1H), 6.73 (d, J=6.8 Hz,2H), 6.90–7.11 (m, 4H), 7.62 (d, J=6.8 Hz, 2H) ppm. MS (DCl/NH₃) m/z 422(M+H)⁺.

Example 38B 3-[4-(4-iodo-phenoxy)-phenoxy]-1-aza-bicyclo[2.2.2]octanehydrochloride

The product of 38A (50.0 mg, 0.12 mmol) in ethyl acetate (5 mL) wastreated with 4M HCl in 1,4-dioxane (0.25 mL, 1.0 mmol) to provide thetitle compound as a solid (52.0 mg, yield, 95%). ¹H NMR (MeOH-d₄, 300MHz) δ 1.77–2.23 (m, 3H), 2.24–2.38 (m, 1H), 2.42–2.64 (m, 1H),3.20–3.49 (m, 6H), 3.65–3.91 (m, 1H), 6.72 (d, J=6.8 Hz, 1H), 7.00 (s,4H), 7.62 (d, J=6.8 Hz, 2H) ppm. MS (DCl/NH₃) m/z 422(M+H)⁺. Anal.Calculated for C₁₉H₂₀INO₂.1.00HCl.0.25H₂O: C, 49.37; H, 4.69; N, 3.03.Found: C, 49.25; H, 4.30; N, 2.96.

Example 39{4-[4-(1-aza-bicyclo[2.2.2oct-3-yloxy)-phenoxy]-phenyl}-hydrazinebis(hydrochloride) Example 39AN-{4-[4-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-phenoxy]-phenyl}-hydrazinecarboxylicacid tert-butyl ester

The product of Example 38A (420 mg, 1.0 mmol) was coupled withtert-butyl carbazate (Aldrich, 158 mg, 1.2 mmol) under the catalysis ofCul (Strem Chemicals, 9.5 mg, 0.05 mmol) with Cs₂CO₃ (Strem Chemicals,489 mg, 1.4 mmol) in DMF (anhydrous, Aldrich, 5 mL) at 80° C. overnight.The mixture was diluted with EtOAc (50 mL) and washed with water (2×10mL). The organic solution was concentrated and the title compound waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f).0.20) as an oil (190 mg, yield, 45%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.46(s, 9H), 1.76–2.16 (m, 3H), 2.20–2.39 (m, 1H), 2.41–2.54 (m, 1H),3.16–3.47 (m, 5H), 3.66–3.86 (m, 1H), 4.70–4.84 (m, 1H), 6.77–6.93 (m,2H), 6.94–7.04 (m, 4H), 7.25–7.48 (m, 2H) ppm. MS (DCl/NH₃) m/z 426(M+H)⁺.

Example 39B{4-[4-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-phenoxy]-phenyl}-hydrazinebis(hydrochloride)

The product of Example 39A (80 mg, 0.19 mmol) was treated with HCl(Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol) in EtOAc (5 mL) at roomtemperature for 10 h to give the title compound as yellow solid (60 mg,yield, 79%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.76–2.20 (m, 3H), 2.21–2.40(m, 1H), 2.40–2.59 (m, 1H), 3.20–3.48 (m, 6H), 3.70–3.85 (m, 1H),6.83–7.19 (m, 8H) ppm. MS (DCl/NH₃) m/z 426(M+H)⁺. Anal. Calculated forC₁₉H₂₃N₃O₂.2.40HCl.0.20H₂O.0.50EtOAc: C, 54.76; H, 6.52; N, 9.12. Found:C, 54.50; H, 6.13; N, 8.84.

Example 403-[4-(2-methyl-3-phenyl-1H-indol-5-yloxy)-phenoxy]-1-aza-bicyclo[2.2.2]octanehydrochloride Example 40A3-[4-(2-methyl-3-phenyl-1H-indol-5-yloxy)-phenoxy]-1-aza-bicyclo[2.2.2]octane

The product of Example 39A (105 mg, 0.25 mmol) was treated with1-phenyl-propan-1-one (Aldrich, 67 mg, 0.5 mmol) and HCl (Aldrich, 4 Min dioxane, 0.5 mL, 2 mmol) in EtOH (3.0 mL) at 80° C. for 10 h. Themixture was concentrated and the title compound was was purified bypreparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. ElutingSolvent, MeCN/H₂O (NH₄HCO₃, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (60 mg, yield, 57%).¹H NMR (300 MHz, CD₃OD) δ 1.45–1.80 (m, 4H), 2.09–2.19 (m, 1H), 2.37 (s,3H), 2.62–2.97 (m, 4H), 3.19–3.44 (m, 1H), 4.34–4.53 (m, 1H), 6.81 (dd,J=8.6, 2.2 Hz, 1H), 6.85–7.04 (m, 4H), 7.09 (d, J=2.4 Hz, 1H), 7.27–7.38(m, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.63 (d, J=7.1 Hz, 2H) ppm; MS(DCl/NH₃) m/z 425 (M+H)⁺.

Example 40B3-[4-(2-methyl-3-phenyl-1H-indol-5-yloxy)-phenoxy]-1-aza-bicyclo[2.2.2]octanehydrochloride

The product of Example 40A (60 mg, 0.14 mmol) was treated with HCl(Aldrich, 4 M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (5 mL) at ambienttemperature for 1 hour to give the title compound as solid (25.0 mg,yield, 39%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.78–2.04 (m, 2H), 2.03–2.21(m, 1H), 2.28–2.37 (m, 1H), 2.37 (s, 3H), 2.45–2.56 (m, 1H), 3.33–3.47(m, 5H), 3.68–3.86 (m, 1H), 4.73–4.83 (m, 1H), 6.81 (dd, J=8.8, 2.4 Hz,1H), 6.88–6.98 (m, 4H), 7.09 J=2.4 Hz, 1 H,) 7.25–7.38 (m, 2H),7.42–7.52 (m, 2H), 7.59–7.69 (m, 2H)ppm. MS (DCl/NH₃) m/z 425(M+H)⁺.Anal. Calculated for C₁₈H₂₈N₂O₂.1.40HCl.0.62H₂O: C, 69.09; H, 6.34; N,5.76. Found: C, 69.43; H, 5.97; N, 5.43.

Example 413-[6-(4-iodo-phenoxy)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octanetri(hydrochloride) Example 41A3-[6-(4-iodo-phenoxy)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane

The product of Example 27C (870 mg, 3.00 mmol) was treatedtrifluroacetic acid (0.46 mL, 6.0 mmol) in MeCN (Aldrich, 10.0 mL) atambient temperature for 10 min. N-lodosuccinimide (Aldrich, 0.742 g, 3.3mmol) was then added and the mixture was stirred at 80° C. for 6 h. Themixture was concentrated. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.35) assolid (270 mg, yield, 21%). ¹H NMR (300 MHz, CD₃OD) δ 1.81–2.17 (m, 3H),2.23–2.40 (m, 1H), 2.47–2.64 (m, 1H), 3.17–3.45 (m, 5H), 3.81 (dd,J=14.1, 8.3 Hz, 1 H), 5.19–5.49 (m, 1H), 7.00(dt, J=8.8, 2.1 Hz, 2H),7.33 (d, J=9.5 Hz, 1H), 7.42 (d, J=9.5 Hz, 1H), 7.76 (dt, J=8.8, 2.1 Hz,2H) ppm; MS (DCl/NH₃) m/z 424 (M+H)⁺.

Example 41B3-[6-(4-iodo-phenoxy)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octanetri(hydrochloride)

The product of Example 41A (20 mg, 0.05 mmol) was treated with HCl(Aldrich, 4 M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (2 mL) at ambienttemperature for 1 hour to give the title compound as solid (20.0 mg,yield, 80%). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.87–2.20 (m, 3H), 2.27–2.47(m, 1H), 2.52–2.65 (m, 1H), 3.31–3.48 (m, 5H), 3.78–3.97 (m, 1H),5.25–5.50 (m, 1H), 6.99 (dt, J=9.1, 2.3 Hz, 2H), 7.34 (d, J=9.5 Hz, 1H),7.43 (d, J=9.5 Hz, 1H), 7.77 (dt, J=9.1, 2.0 Hz, 2H) ppm. MS (DCl/NH₃)m/z 424(M+H)⁺. Anal. Calculated for C₁₇H₁₈IN₃O₂.3.55HCl.1.80H₂O: C,34.90; H, 4.33; N, 7.18. Found: C, 34.53; H 3.95; N, 6.83.

Example 422-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-8-iodo-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazocinefumarate Example 42A2,8-diiodo-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazocine

The mixture of 4-iodo-phenylamine (Aldrich, 6.57 g, 30 mmol) andparaformaldehyde (Aldrich, 1.80 g, 60 mmol) in trifluroacetic acid(Aldrich, 60 mL) was stirred at ambient temperature for 15 hour. It wasthen concentrated , dissolved in water (10 mL) and neutralized withNH₃.H₂O till pH=9. The mixture was extracted with EtOAc (3×50 mL). Theextracts were combined and concentrated. The title compound was purifiedby chromatography (SiO₂, hexane: EtOAc, 50:50, R_(f). 0.40) as solid(2.70 g, yield, 38%).¹H NMR (300 MHz, CDCl₃) δ 4.09 (d, J=17.0 Hz, 2H),4.26 (s, 2H), 4.63 (d, J=16.6 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 7.16–7.31(m, 2H), 7.47 (dd, J=8.5, 2.0 Hz, 2H) ppm. MS (DCl/NH₃) 475 (M+H)⁺.

Example 42B2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-8-iodo-6H,12H-5,11-methano-dibenzo[b,f][1,

The product of example 42A (474 mg, 1.0 mmol) was coupled with the3-hydroxy quinuclidine (Aldrich, 254 mg, 2.0 mmol) under the catalysisof Cul (Strem Chemicals, 19.0 mg, 0.1 mmol) and 1,10-phenanthroline(Aldrich, 36 mg, 0.2 mmol) with Cs₂CO₃ (Aldrich, 652 mg, 2.0 mmol) intoluene (5 mL) at 110° C. for 40 hours according to the procedure ofExample 14A. The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH (with v. 2% NH₃.H₂O, 90:10, R_(f). 0.30) as solid (120 mg,yield, 25%).¹H NMR (300 MHz, CDCl₃) δ 1.48–1.65 (m, 2H), 1.66–2.08 (m,3H), 2.08–2.18 (m, 1H), 2.68–3.10 (m, 5H), 3.12–3.37 (m, 1H), 3.95–4.18(dd, J=16.9, 6.4 Hz, 2H), 4.18–4.34 (m, 3H), 4.61 (dd, J=17.3, 11.3 Hz,2H), 6.36 (d, J=2.7 Hz, 1H), 6.69 (dd, J=8.8, 2.7 Hz, 1H), 6.88 (d,J=8.5 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.45 (dd,J=8.5, 1.7 Hz, 1H) ppm. MS (DCl/NH₃) 474 (M+H)⁺.

Example 42C2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-8-iodo-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazocinefumarate

The product of Example 42B (30 mg, 0.06 mmol) was treated with fumaricacid (11.6 mg, 0.1 mmol) in EtOH/MeOH (v. 10/1, 2 mL) at roomtemperature for 10 h to give the title compound (28 mg, yield, 75%). ¹HNMR (MeOH-d₄, 300 MHz) δ 1.72–2.12 (m, 3H), 2.13–2.33 (m, 1H), 2.33–2.49(m, 1H), 3.23–3.37 (m, 5H), 3.68 (dd, J=13.7, 8.3 Hz, 1H), 4.11 (t,J=19.0 Hz, 2H), 4.29 (s, 2H), 4.62 (dd, J=16.8, 12.0 Hz, 2H), 4.69–4.80(m, 1H), 6.57 (dd, J=5.6, 2.9 Hz, 1H), 6.69 (s, 2H), 16.8, (dt, J=4.4,2.7Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 7.29 (d,J=2.0 Hz, 1H), 7.47 (dd, J=8.5, 2.0 Hz, 1H) ppm. MS (DCl/NH₃) m/z474(M+H)⁺. Anal. Calculated for C₂₂H₂₄IN₃O.1.30C₄H₄O₄.0.70H₂O: C, 51.30;H, 4.84; N, Found: C, 51.49; H, 4.84; N, 6.22.

Example 432-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazoctri(hydrochloride) Example 43A2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazoc

The product of example 42B (90 mg, 0.19 mmol) was hydrogenated under thecatalysis of Pd/C (Aldrich, 10 wt. %, 20 mg) in EtOH (10 mL) under H2 atambient temperature for 2 h. The catalyst was then filtered off. Theethanol solution was concentrated, treated with 1N NaOH (1 mL) andextracted with CHCl₃/iPrOH (v. 10:1, 3×10 mL). The extracts werecombined and concentrated to give the title compound as yellow solid (60mg, yield, 91%).¹H NMR (300 MHz, CDCl₃) δ 1.52–1.85 (m, 3H), 1.91–2.03(m, 1H), 2.02–2.15 (m, 1H), 2.58–2.97 (m, 5H), 3.14–3.28 (m, 1H), 4.13(t, J=16.3 Hz, 2H), 4.31 (s, 2H), 4.34–4.44 (m, 1H), 4.64 (d, J=16.6 Hz,2H), 6.49 (s, 1H), 6.75 (dd, J=8.6, 2.9 Hz, 1H), 6.89–7.20 (m, 5H) ppm.MS (DCl/NH₃) 348 (M+H)⁺.

Example 43B2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-6H,12H-5,11-methano-dibenzo[b,f][1,5]diazoctri(hydrochloride)

The product of Example 43A (60 mg, 0.17 mmol) was treated with HCl(Aldrich, 4 M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (5 mL) at roomtemperature for 10 h to give the title compound (70.0 mg, yield, 90%).¹H NMR (MeOH-d₄, 300 MHz) δ 1.72–2.28 (m, 4H), 2.36–2.57 (m, 1H),3.19–3.43 (m, 6H), 3.79 (dd, J=14.2, 8.5 Hz, 1H), 4.50 (dd, J=15.9, 8.1Hz, 2H), 4.88–5.15 (m, 4H), 6.86 (t, J=2.5 Hz, 1H), 7.07 (dt, J=8.8, 2.4Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.22–7.32 (m, 1H), 7.36–7.45 (m, 2H),7.48 (d, J=8.8 Hz, 1H) ppm. MS (DCl/NH₃) m/z 348 (M+H)⁺. Anal.Calculated for C₂₂H₂₅N₃O.3.35C₄H₄O₄.2.05H₂O: C, 2.17; H, 6.46; N, 8.30.Found: C, 51.78; H, 6.06; N, 8.02.

Example 44 Determination of Biological Activity

To determine the effectiveness of representative compounds of thisinvention as α7 nAChRs, the compounds of the invention were evaluatedaccording to the [3H]-methyllycaconitine (MLA) binding assay andconsidering the [3H]-cytisine binding assay, which were performed asdescribed below.

[3H]-Cytisine Binding

Binding conditions were modified from the procedures described inPabreza L A, Dhawan, S, Kellar K J, [³H]-Cytisine Binding to NicotinicCholinergic Receptors in Brain, Mol. Pharm. 39: 9–12, 1991. Membraneenriched fractions from rat brain minus cerebellum (ABS Inc.,Wilmington, Del.) were slowly thawed at 4° C. washed and resuspended in30 volumes of BSS-Tris buffer (120 mM NaCl/5 mM KCl/2 mM CaCl₂/2 mMMgCl₂/50 mM Tris-Cl, pH 7.4, 4° C.). Samples containing 100–200 μg ofprotein and 0.75 nM [3H]-cytisine (30 C_(i)/mmol; Perkin Elmer/NEN LifeScience Products, Boston, Mass.) were incubated in a final volume of 500μL for 75 minutes at 4° C. Seven log-dilution concentrations of eachcompound were tested in duplicate. Non-specific binding was determinedin the presence of 10 μM (−)-nicotine. Bound radioactivity was isolatedby vacuum filtration onto prewetted glass fiber filter plates(Millipore, Bedford, Mass.) using a 96-well filtration apparatus(Packard Instruments, Meriden, Conn.) and were then rapidly rinsed with2 mL of ice-cold BSS buffer (120 mM NaCl/5 mM KCl/2 mM CaCl₂/2 mMMgCl₂). Packard MicroScint-20® scintillation cocktail (40 μL) was addedto each well and radioactivity determined using a Packard TopCount®instrument. The IC₅₀ values were determined by nonlinear regression inMicrosoft Excel® software. K_(i) values were calculated from the IC₅₀susing the Cheng-Prusoff equation, where K_(i)=IC₅₀/1+[Ligand]/K_(D)].

[3H]-Methyllycaconitine (MLA) Binding

Binding conditions were similar to those for [3H]-cytisine binding.Membrane enriched fractions from rat brain minus cerebellum (ABS Inc.,Wilmington, Del.) were slowly thawed at 4° C., washed and resuspended in30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mMMgCl₂, and 50 mM Tris-Cl, pH 7.4, 22° C.). Samples containing 100–200 μgof protein, 5 nM [3H]-MLA (25 C_(i)/mmol; Perkin Elmer/NEN Life ScienceProducts, Boston, Mass.) and 0.1% bovine serum albumin (BSA, Millipore,Bedford, Mass.) were incubated in a final volume of 500 μL for 60minutes at 22° C. Seven log-dilution concentrations of each compoundwere tested in duplicate. Non-specific binding was determined in thepresence of 10 μM MLA. Bound radioactivity was isolated by vacuumfiltration onto glass fiber filter plates prewetted with 2% BSA using a96-well filtration apparatus (Packard Instruments, Meriden, Conn.) andwere then rapidly rinsed with 2 mL of ice-cold BSS. PackardMicroScint-20® scintillation cocktail (40 μL) was added to each well andradioactivity was determined using a Packard TopCount® instrument. TheIC₅₀ values were determined by nonlinear regression in Microsoft Excel®software. K_(i) values were calculated from the IC₅₀s using theCheng-Prusoff equation, where K_(i)=IC₅₀/1+[Ligand]/K_(D)].

Compounds of the invention had Ki values of from about 1 nanomolar toabout 10 micromolar when tested by the MLA assay, many having a K_(i) ofless than 1 micromolar. [3H]-Cytisine binding values of compounds of theinvention ranged from about 50 nanomolar to at least 100 micromolar. Thedetermination of preferred compounds typically considered the K_(i)value as measured by MLA assay in view of the K_(i) value as measured by[3H]-cytisine binding, such that in the formulaD=K_(i 3H-cytisine)/K_(i MLA), D is about 50. Preferred compoundstypically exhibited greater potency at α7 receptors compared to α4β2receptors.

Compounds of the invention are α7 nAChRs ligands that modulate functionof α7 nAChRs by altering the activity of the receptor. The compounds canbe inverse agonists that inhibit the basal activity of the receptor orantagonists that completely block the action of receptor-activatingagonists. The compounds also can be partial agonists that partiallyblock or partially activate the α7 nAChR receptor or agonists thatactivate the receptor.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1. A compound of the formula (I):

or a pharmaceutically acceptable salt, ester, or amide, thereof,wherein: A is N or N⁺—O⁻; n is 0, 1, or 2; X¹ is selected from the groupconsisting of O, S, and —N(R¹)— X² is selected from the group consistingof O, S, —N(R¹)—, —N(Ar²)—, and —N(R²)C(O)—; Ar¹ is a group of theformula:

Ar² is cycloalkyl, or Ar² is a group of the formula:

Y¹, Y², Y³, and Y⁴ are each independently selected from the groupconsisting of N and —CR³; Y⁵, Y⁶, Y⁷, Y⁸, and Y⁹ are each independentlyselected from the group consisting of N and —C(R⁶); Y¹⁰ is selected fromthe group consisting of —N(R⁹), O and S; Y¹¹, Y¹², Y¹³, and Y¹⁴ are eachindependently selected from the group consisting of N, C and —C(R⁶);provided that one of Y¹¹, Y¹², Y¹³, and Y¹⁴ is C and formula (c) isattached to X² or the nitrogen atom of —N(Ar²)— through one of Y¹¹, Y¹²,Y¹³, and Y¹⁴ that is represented by C; Z¹ is independently selected fromO, S, —N(R⁹), —C(R¹⁰) and —C(R¹⁰)(R^(10a)); Z² and Z³ are eachindependently selected from the group consisting of N, C and —Cis—C(R¹⁰), provided that zero or one of Z² and Z³ is C; and provided thatwhen Z¹ is —C(R¹⁰), then Z² and Z³ are other than C; and furtherprovided that when one of Z² or Z³ is C, then Z¹ is other than —C(R¹⁰);Z⁴, Z⁵, Z⁶, and Z⁷ are independently selected from the group consistingof C and —C(R¹¹); provided that zero or one of Z⁴, Z⁵, Z⁶, and Z⁷ is C;wherein when one of Z⁴, Z⁵, Z⁶, and Z⁷ is C, then formula (d) isattached to X² or the nitrogen atom of —N(Ar²)— through one of Z⁴, Z⁵,Z⁶, and Z⁷ that is represented by C; Z¹ is other than —C(R¹⁰); and Z²and Z³ are other than C; or when Z¹ is —C(R¹⁰), then formula (d) isattached to X² or the nitrogen atom of —N(Ar²)— through the C atom of—C(R¹⁰); Z⁴, Z⁵, Z⁶, and Z⁷ are —C(R¹¹); and Z² and Z³ are other than C;or when one of Z² or Z³ is C, then formula (d) is attached to X² or thenitrogen atom of —N(Ar²)— through Z² or Z³ represented by C; Z¹ is otherthan —C(R¹⁰); and Z⁴, Z⁵, Z⁶, and Z⁷ are —C(R¹¹); R¹ and R² at eachoccurrence are each independently selected from the group consisting ofhydrogen and alkyl; R³ at each occurrence is independently selected fromthe group consisting of hydrogen, halo, alkyl, aryl, —OR⁴, and —NHR⁵; R⁴and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, andarylsulfonyl; R⁶ at each occurrence is independently selected from thegroup consisting of hydrogen, halo, haloalkyl, alkyl, aryl,alkylcarbonyl, —OR⁷, and —NHR⁸; R⁷ and R⁸ are each independentlyselected from the group consisting of hydrogen, alkyl,1-aza-bicyclo[2.2.2]oct-3-yl, amino, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, and arylsulfonyl; and R⁹, R¹⁰, R^(10a), R¹¹, and R¹² ateach occurrence are each independently selected from the groupconsisting of hydrogen, alkyl, aryl, alkylcarbonyl, and arylcarbonyl. 2.The compound of claim 1, wherein Ar¹ is selected from the groupconsisting of:

wherein R³ is as defined in claim
 1. 3. The compound of claim 1, whereinAr² is selected from the group consisting of cycloalkyl,

wherein r is 0, 1, 3, 4 or 5; s is 0, 1, 2 or 3; t is 0, 1, 2, 3 or 4;Y¹⁰ is selected from the group consisting of —N(R⁹), O and S; one of Y¹²and Y¹³ is N, C or —C(R⁶), and the other is C or —C(R⁶); Y¹¹ and Y¹⁴ areeach independently selected from the group consisting of C and —CR⁶;provided that one of Y¹¹ and Y¹⁴ or one of Y¹² and Y¹³ is C and formula(c) is attached to X² or the nitrogen atom of —N(Ar²)— through one ofY¹¹, Y¹², Y¹³, and Y¹⁴ that is represented by C; and Z¹, Z², Z³, Z⁴, Z⁵,Z⁶, Z⁷, R⁶, and R⁹ are as defined in claim
 1. 4. The compound of claim1, wherein Ar² is selected from the group consisting of cyclohexyl,

wherein: Z² and Z³ are independently N, C or —C(R¹²); provided that zeroor one of Z² and Z³ is C; Z⁴, Z⁵, Z⁶, and Z⁷ are independently selectedfrom the group consisting of C and —C(R¹¹); provided that zero or one ofZ⁴, Z⁵, Z⁶, and Z⁷ is C; wherein when one of Z⁴, Z⁵, Z⁶, and Z⁷ is C,then each of formulas (4-vi) and (4-vii) is attached to X2 or thenitrogen atom of N(Ar2)- through one of Z⁴, Z⁵, Z⁶ and Z⁷ that isrepresented by C, and Z² and Z³ are each —C(R¹²); or when one of Z² orZ³ is C, then each of formulas (4-vi) and (4-vii) is attached to X² orthe nitrogen atom of —N(Ar²)— through Z² or Z³ represented by C, and Z⁴,Z⁵, Z⁶ and Z⁷ are —C(R¹¹); R⁶ is selected from the group consisting ofhydrogen, fluoro, trifluoromethyl, hydroxy,1-aza-bicyclo[2.2.2]oct-3-yloxy, 1-aza-bicyclo[2.2.2]oct-3-ylamino,isopropoxy, bromo, chloro, iodo, methyl, hydrazino, and amino; R¹² isselected from the group consisting of hydrogen, methyl and phenyl; andR⁹ and R¹¹ are as defined in claim
 1. 5. The compound of claim 1, or apharmaceutically acceptable salt, ester or amide, thereof, selected fromthe group consisting of: 3-(3-phenoxyphenoxy)quinuclidine;3-(4-phenoxyphenoxy)quinuclidine; (3R)-3-(4-phenoxyphenoxy)quinuclidine;(3S)-3-(4-phenoxyphenoxy)quinuclidine;3-{4-[4-(trifluoromethyl)phenoxy]phenoxy}quinuclidine;3-[4-(4-fluorophenoxy)phenoxy]quinuclidine;4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenoxy]phenol;4-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenoxy}phenol;4-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]thio}phenol;4-({4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}thio)phenol;3-{4-[(4-isopropoxyphenyl)thio]phenoxy}quinuclidine;3-[4-(pyridin-3-yloxy)phenoxy]quinuclidine;3-[4-(thien-3-yloxy)phenoxy]quinuclidine;3-{4-[(5-bromopyrimidin-2-yl)oxy]phenoxy}quinuclidine;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-phenylamine;N-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-N-phenylamine;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]pyridin-3-amine;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]benzamide;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-cyclohexylamine;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-dithien-3-ylamine;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-1,3-thiazol-2-yl-1,3-thiazol-2-amine;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N,N-bis(1-benzothien-3-yl)amine;1-(5-{[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]amino}thien-2-yl)ethanone;N-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-N-(4-methylthien-3-yl)amine;3-[(6-phenoxypyridazin-3-yl)oxy]quinuclidine;3-[(5-phenoxypyridin-2-yl)oxy]quinuclidine;3-[(5-phenoxypyrimidin-2-yl)oxy]quinuclidine;N-(4-phenoxyphenyl)quinuclidin-3-amine;N-[4-(4-chlorophenoxy)phenyl]quinuclidin-3-amine;N-[4-(4-methylphenoxy)phenyl]quinuclidin-3-amine;N-[4-(4-aminophenoxy)phenyl]quinuclidin-3-amineN-1-azabicyclo[2.2.2]oct-3-yl-N′-phenylbenzene-1,4-diamine;3-[(4-phenoxyphenyl)thio]quinuclidine;N-[4-(1-azabicyclo[2.2.2]oct-3-ylthio)phenyl]-N-phenylamine;4,4′-di(1-aza-bicyclo[2.2.2]oct-3-yloxy)-diphenyl ether;4,4′-di[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-diphenyl thioether;4,4′-di(1-aza-bicyclo[2.2.2]oct-3-yl-amino)-diphenyl thioether;3-[4-(4-iodo-phenoxy)-phenoxy]-1-aza-bicyclo[2.2.2]octane;{4-[4-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-phenoxy]-phenyl}-hydrazine;3-[4-(2-methyl-3-phenyl-1H-indol-5-yloxy)-phenoxy]-1-aza-bicyclo[2.2.2]octane;and 3-[6-(4-iodo-phenoxy)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane.6. A compound of the formula (II):

or a pharmaceutically acceptabelsalt,ester, or amide, thereof, wherein:G is N or N⁺—O³¹ ; X³ is —N(R¹⁴)—, O, or S; m is 0, 1, or 2; R¹⁴ ishydrogen or alkyl; and R¹³ is hydrogen alkyl, or halogen.
 7. The compundof claim 6, or a pharmaceutically acceptable salt, ester, or amide,thereof, selected from the group consisting of:2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-8-iodo-6H, 12H-5,11-methano-dibanzo[b,f][1,5]diazocine; and2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-6H, 12H-5,11-methano-dibenzo[b,f][1,5]diazocine.
 8. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 1in combination with a pharmaceutically acceptable carrier.
 9. A methodof treating a condition or disorder selected from the group consistingof attention deficit disorder, attention deficit hyperactivity disorder(ADHD), Alzheimer's disease (AD), mild cognitive impairment, seniledementia, AIDS dementia, dementia associated with Lewy bodies, dementiaassociated with Down's syndrome, diminished CNS function associated withtraumatic brain injury, comprising the step of administering a compoundof claim
 1. 10. The method according to claim 9, wherein the conditionor disorder is a cognitive disorder.
 11. The method according to claim9, in combination with an atypical antipsychotic.
 12. The method oftreating schizophrenia, comprising the step of administering a compoundof claim 1.